Compounds for preventing, inhibiting, or treating cancer, aids and/or premature aging

ABSTRACT

The manufacture and use of compounds of formula (Ia) or a pharmaceutically acceptable salt thereof for preventing, inhibiting or treating cancer, AIDS and/or premature aging. The compounds of formula (Ia) being: 
                         
where:
         R independently represents a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, a —CN group, a hydroxyl group, a —COOR 1  group, a (C 1 -C 3 )fluoroalkyl group, a —NO 2  group, a —NR 1 R 2  group, or a (C 1 -C 3 )alkoxy group;   R′ is a hydrogen atom, a halogen atom, a (C 1 -C 3 )alkyl group, a —NO 2  group, a (C 1 -C 3 )alkoxy group, or a —NR 1 R 2  group; and   R 1  and R 2  are a hydrogen atom or a (C 1 -C 3 ) alkyl group.

This is a divisional of U.S. application Ser. No. 15/486,836 filed Apr.13, 2017, which is a continuation-in-part of:

-   -   U.S. application Ser. No. 14/789,149 filed Jul. 1, 2015,    -   U.S. application Ser. No. 14/789,250 filed Jul. 1, 2015,    -   U.S. application Ser. No. 14/256,334 filed Apr. 18, 2014, and    -   U.S. application Ser. No. 13/377,753 filed Jun. 4, 2012;

U.S. application Ser. No. 14/789,149 filed Jul. 1, 2015, is acontinuation of U.S. application Ser. No. 14/087,762 filed Nov. 22,2013, now U.S. Pat. No. 9,108,919, which is a continuation ofapplication Ser. No. 13/377,745 filed Jul. 5, 2012, now abandoned, whichis a National Stage Application of PCT/IB2010/052560 filed Jun. 14,2010, and claims the benefit of U.S. Provisional Application Nos.61/186,552 and 61/186,544 and European Application Nos. 09305540.8 and09162630.9, all of which were filed on Jun. 12, 2009;

U.S. application Ser. No. 14/789,250 filed Jul. 1, 2015, is acontinuation of U.S. application Ser. No. 13/377,760 filed Jul. 2, 2012,now U.S. Pat. No. 9,145,367, which is a National Stage Application ofPCT/IB2010/052651 filed Jun. 14, 2010, and claims the benefit of U.S.Provisional Application Nos. 61/186,544 and 61/186,552 and EuropeanApplication Nos. 09162630.9 and 09305540.8, all of which were filed onJun. 12, 2009;

U.S. application Ser. No. 14/256,334 filed Apr. 18, 2014 is acontinuation of U.S. application Ser. No. 13/377,760 filed Jul. 2, 2012,now U.S. Pat. No. 9,145,367, which is a National Stage Application ofPCT/IB2010/052651 filed Jun. 14, 2010, and claims the benefit of U.S.Provisional Application Nos. 61/186,544 and 61/186,552 and EuropeanApplication Nos. 09162630.9 and 09305540.8, all of which were filed onJun. 12, 2009; and

U.S. application Ser. No. 13/377,753 filed Jun. 4, 2012 is a NationalStage Application of PCT/IB2010/052652 filed Jun. 14, 2010, and claimsthe benefit of U.S. Provisional Application Nos. 61/186,544 and61/186,552 and European Application Nos. 09162630.9 and 09305540.8, allof which were filed on Jun. 12, 2009. The entire disclosures of each ofthe above-mentioned prior applications are hereby incorporated byreference herein in their entireties.

FIELD OF THE INVENTION

The present disclosure is generally directed to the manufacture and useof compounds described herein for preventing, inhibiting or treatingcancer, AIDS and/or premature aging.

BACKGROUND OF THE INVENTION

Cancer

In most cancers, mortality is not due to the primary tumor but rather tothe derived metastases. This malignant progression is clinically definedby the appearance of metastatic cells. Tumor metastases are typicallydefined by a primary loss of cell adhesion and an increase of cellmotility, which allows for invasive cell to leave the initial tumor siteand colonize various target tissues.

Metastases are considered as a recurrent feature of uncontrolledmalignant progression of cancer. During this process, tumor cellscomplete their malignant transformation by increasing their migratorycapacity. Cancer cells can then disseminate and establish new tumor fociin far away sites. This event is termed “metastatic cascade,” which, asindicated immediately above, is marked by invasion of tissues around thetumor, venous or lymphatic intravasation, migration and establishment ofnew tumors in distant places of an organism that may escape from allinnate defense mechanisms.

Because no efficient therapeutic options presently exist for thetreatment or prevention of metastatic tumors, metastatic invasion amajor cause of death worldwide. Due to the frequency of cancersdiagnosed at the metastatic stage and the lack of viable therapeuticoptions at this stage of the disease, the development of molecules thatspecifically target metastatic invasion is crucial for a majorbreakthrough in cancer treatments.

The compounds and methods of use as described herein are consistent withnumerous published reports during the last twenty years that demonstratea link between changes in RNA alternative splicing and metastaticinvasion, which has opened new avenues for therapeutic strategies.

AIDS

Certain indole derivative compounds such as ellipticine derivatives andaza-ellipticine derivatives are already known as intercalating moleculesfor correcting dysfunctions in gene expression, notably in DNAreplication. They have been more specifically described for treatingdiseases such as cancer, leukemia or AIDS (see in particular patents FR2 627 493, FR 2 645 861, FR 2 436 786).

Concerning current treatments for AIDS, the various approaches aimed atreducing viral load in patients infected by HIV utilize moleculesintended to inhibit the enzymatic activity of viral reversetranscriptase or of the protease involved in virus protein maturation.Regarding reverse transcriptase inhibitors, these can be nucleosidic(NRTIs), non-nucleosidic (NNRTIs) or nucleotidic in nature. The purposeof using these compounds is to prevent a DNA copy of the retroviralgenome from being produced and, consequently, from being integrated intothe genome of the host cell. Protease inhibitors (PIs) interfere withthe proper maturation of viral proteins and cause the production ofincomplete particles with altered infectious capacities. There isanother type of anti-retroviral compound used for its ability to preventviruses from entering the cell. These entry inhibitors can be eitherpeptides that interfere with the fusion of viral glycoproteins gp41 orgp120 with the membrane of CD4 cells or molecules that target HIVcellular co-receptors CCR5 and CXCR4. The absence of cellular proteinsresembling HIV integrase has also been exploited to develop novelanti-HIV molecules that inhibit this enzymatic activity. Although anumber of integrase inhibitors are in the clinical trial phase, nomolecule is yet available on the market.

The intracellular splicing process consists of eliminating introns inpre-messenger RNAs to produce mature messenger RNAs that can be used bythe translation mechanism of the cell (SHARP, Cell, vol. 77, p. 805-815,1994). In the case of alternative splicing, the same precursor can bethe source of messenger RNAs coding for proteins with distinct functions(BLACK, Annu. Rev. Biochem. vol. 72, p. 291-336, 2003). The preciseselection of 5′ and 3′ splicing sites is thus a mechanism that generatesdiversity and that can lead to the regulation of gene expressionaccording to the type of tissue or during the development of anorganism. The factors involved in this selection include a family ofproteins called SR, characterized by the presence of one or two RNArecognition motifs (RRM) and a domain rich in arginine and serineresidues called an RS domain (MANLEY & TACKE, Genes Dev., vol. 10, p.1569-1579, 1996). By binding to short exon or intron sequences of thepre-mRNA, called ESE (exonic splicing enhancer) or ISE (intronicsplicing enhancer), SR proteins are able to activate, in adose-dependant manner, sub-optimal splicing sites and to enable theinclusion of exons (GRAVELEY, RNA, vol. 6, p. 1197-1211, 2000). Theactivity of an SR protein in alternative splicing is specific insofar asthe inactivation of the corresponding gene is lethal (WANG et al., Mol.Cell, vol. 7, p. 331-342, 2001).

Sequencing of the human genome and analysis of EST (expressed sequencetag) banks has revealed that 65% of genes are expressed in the form ofalternatively spliced variants (EWING & GREEN, Nat. Genet., vol. 25, p.232-234, 2000; JOHNSON et al., Science, vol. 302, p. 2141-2144, 2003).This mechanism is thus a favored target of modifications that can affectthe factors involved in regulating splicing and of mutations that affectthe sequences necessary for this regulation. At present, it is estimatedthat roughly 50% of the point mutations responsible for genetic diseasesinduce aberrant splicing. These mutations can interfere with splicing byinactivating or creating splicing sites, but also by modifying orgenerating regulating elements such as splicing enhancers or splicingsilencers in a particular gene (CARTEGNI et al., Nat. Rev. Genet., vol.3, p. 285-298, 2002; TAZI et al., TIBS, vol. 40, p. 469-478, 2005).

The strategies currently developed to correct these splicing defectsrest on the use of various types of molecules (TAZI et al., cited above,2005).

One strategy aimed at developing novel molecules to correct or eliminateabnormal splicing, for example, rests on the overexpression of proteinsthat interfere with this type of splicing (NISSIM-RAFINIA et al., Hum.Mol. Genet., vol. 9, p. 1771-1778, 2000; HOFINANN et al., Proc. Natl.Acad. Sci. U.S.A., vol. 97, p. 9618-9623, 2000).

Other strategies rest on the use of antisense oligonucleotides (SAZANIet al., Nat. Biotechnol., vol. 20, p. 1228-1233, 2002; SAZANI & KOLE,Prog. Mol. Subcell. Biol., vol. 31, p. 217-239, 2003) or of PNA(CARTEGNI et al., Nat. Struct. Biol., vol. 10, p. 120-125, 2003)enabling, respectively, the inhibition or activation of a splicingevent.

Yet another strategy rests on the identification of compounds thatinfluence the splicing efficiency of the pre-mRNA of interest (ANDREASSIet al., Hum. Mol. Genet., vol. 10, p. 2841-2849, 2001).

Lastly, a strategy based on the use of trans-splicing to replace mutantexons has been described (LIU et al., Nat. Biotechnol., vol. 20, p.47-52, 2002).

One of the disadvantages of the developed strategies cited above tocorrect or eliminate abnormal splicing is their production cost. Indeed,the cost of producing antisense oligonucleotides that must be modifiedto improve their stability, and that of PNA molecules, is high.

Another disadvantage of the developed strategies cited above is thatthey require the use of expression vectors, such as, for example, forthe strategy based on the use of trans-splicing.

International application WO05023255, under French priority ofapplications FR0310460 and FR0400973, filed by the Applicant, disclosedthe use of indole derivatives to treat diseases related to thepre-messenger RNA splicing process in the cell.

Thus it was recently shown that certain indole derivatives proveparticularly effective in treating metastatic cancer and in treatingAIDS (BAKKOUR et al., PLoS Pathogens, vol. 3, p. 1530-1539, 2007).

However, the compounds described have a flat structure with four ringsthat have the disadvantage of intercalating between DNA bases and canthus lead to cellular toxicity.

Premature Aging

Premature aging may be encountered in patients suffering from variousdiseases and in particular from the Hutchinson-Gilford progeria syndrome(HGPS) and from the HIV infection.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorderphenotypically characterized by many features of premature aging. It isclinically characterized by postnatal growth retardation, midfacehypoplasia, micrognathia, premature atherosclerosis, absence ofsubcutaneous fat, alopecia and generalized osteodysplasia (Khalifa,1989—Hutchinson-Gilford progeria syndrome: report of a Libyan family andevidence of autosomal recessive inheritance. Clin. Genet. 35, 125-132.).At birth, the appearance of patients is generally normal, but by 1 yearof age patients show severe growth retardation, balding andsclerodermatous skin changes. They average about 1 m in height andusually weigh less than 15 kg even as teenagers. The age at death rangesfrom 7 to 28 years, with a median of 13.4 years. Over 80% of deaths aredue to heart attacks or congestive heart failure.

Premature aging syndrome has been observed in patients suffering fromHIV infections. One mechanical pathway underlying said premature agingcould be associated, as for the HGPS and as exposed beneath, with anaberrant splicing of the nuclear lamin A gene. Indeed it has recentlybeen hypothesized that protease inhibitors against HIV also block thetransformation of prelamin A into lamin A as it turned out in HGPS.

Most of the patients suffering from premature aging carry a heterozygoussilent mutation that activates the use of a cryptic 5′ splice site inexon 11 of LMNA pre-mRNA. This aberrant splicing event leads to theproduction of a truncated protein (progerin) with a dominant negativeeffect which is responsible for the observed phenotype (DeSandre-Giovannoli et al., 2003—Lamin A truncation in Hutchinson-Gilfordprogeria. Science 300, 2055/Pendas et al., 2002a—Defective prelamin Aprocessing and muscular and adipocyte alterations in Zmpste24metalloproteinase-deficient mice. Nat. Genet. 31, 94-99.).

Most of the premature aging syndromes in particular associated withHutchinson-Gilford progeria and HIV infection are due to a recurrent, denovo point mutation in LMNA exon 11: c.1824C>T. This mutation islocalized in the part of the gene specifically encoding lamin A (DeSandre-Giovannoli et al., 2003/De Sandre-Giovannoli and Levy,2006—Altered splicing in prelamin A-associated premature agingphenotypes. Prog. Mol. Subcell. Biol. 44, 199-232). Its predicted effectis a silent amino acid change at codon 608 (p.G608G). In fact, thissequence variation is not silent as it occurs in a probable exonsplicing enhancer. As a result, a cryptic splice site is activated intranscripts issued from the mutated allele, which is located 5nucleotides upstream of the mutation.

So far, therapeutic approaches have been mainly focused on progerinwhich is attached to a lipid anchor (a farnesyl lipid anchor). Thislipid anchor is attached to progerin by a specific cellular enzyme,protein farnesyltransferase. Experiments in mouse models suggest thatfarnesyltransferase inhibitors (FTIs) may have beneficial effects inhumans with progeria (Fong et al., 2006—A protein farnesyltransferaseinhibitor ameliorates disease in a mouse model of progeria. Science 311,1621-1623). More recently, Nicolas Levy's team has used a combination ofa statin and an aminobisphosphonate to prevent the fixation of the fattyacid to the progerin, and thus reduce its toxicity (Varela et al.,2008—Combined treatment with statins and aminobisphosphonates extendslongevity in a mouse model of human premature aging. Nat. Med. 14,767-772.).

In WO2006/081444 has been reported a method for reducing at least onecellular defect in a cell from a subject susceptible to a disease orcondition characterized by farnesylation on an abnormally farnesylatedform of a lamin, comprising administering to the cell a therapeuticallyeffective dose of farnesylstransferase inhibitor.

It has been recently reported in WO2008/003864 the use of ahydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and afarnesyl-pyrophosphate synthase inhibitor, or one of their associatedphysiologically acceptable salts, in the preparation of a composition,for use in the treatment of human or animal, pathological ornonpathological situations related to the accumulation and/or thepersistence of prenylated proteins in cells, such as during progeria,restrictive dermopathy or physiological aging.

In WO 2008/115870 substituted quinoline are described, which are usefulfor treating cancer.

In US 2008/0161353 other substituted quinoline are disclosed as agentsto treat neurological conditions.

SUMMARY OF THE INVENTION

In certain aspects, the compounds described herein may be administeredin methods of preventing, inhibiting or treating cancer, AIDS andpremature aging. For example, such methods can include administering aneffective amount of a compound selected from the group consisting of

or any derivative thereof as described below or one of itspharmaceutically acceptable salts to a patient. As described in greaterdetail below, the compounds described herein can be included inpharmaceutical compositions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is schematic representation of the cloning of mutant and wildtype constructs carried out using a TOPO-TA cloning vector in which isinserted a minigene containing 142 nts of β-Globin first exon, 130 ntsβ-Globin first intron, 270 nts LMNA exon 11 either wild type or mutant,322 nts intron 11 and 46 nts exon 12; FIG. 1b is an illustration of theresults of such experiments (i.e., using this system the splicing eventactivated by the GGC>GGT mutation in exon 11 of the LMNA gene wasconfirmed by transfections in cultured HeLa cells (see lanes WT andMut)); and FIG. 1c illustrates the results of transfection experimentsof minigene constructs containing or not the point mutation demonstratedthat like in Progeria patients the mutation leads to a switch from theuse of the normal splice site (intron 11 position 1) to the use of thecryptic splice site upstream of the mutation (exon 11 position 1819).

FIG. 2a is schematic representation of the construction of a plasmid inwhich exon 11, intron 11 and part of exon 12 of LMNA gene were fusedwith luciferase cDNA; FIG. 2b is an illustration of the results ofLuciferase assays; and FIG. 2c is an illustration of the results ofRT-PCR.

DETAILED DESCRIPTION OF THE INVENTION Embodiment I (Cancer)

According to a first aspect, the subject-matter described herein relatesto a compound of formula (I)

-   -   wherein:

means an aromatic ring wherein V is C or N and when V is N, V is in anortho, meta or para position with respect to Z, i.e. forms respectivelya pyridazine, a pyrimidine or a pyrazine group,

-   -   R independently represents a hydrogen atom, a halogen atom or a        group chosen among a —CN group, a hydroxyl group, a —COOR₁        group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group,        a —NO₂ group, a —NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy        group and a (C₁-C₃)alkyl group, the alkyl being optionally        mono-substituted by a hydroxyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   n is 1, 2 or 3,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a morpholinyl or a morpholino group, a        N-methylpiperazinyl group, a (C₁-C₃)fluoroalkyl group, a        (C₁-C₄)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   Z is N or C,    -   Y is N or C,    -   X is N or C,    -   W is N or C,    -   T is N or C,    -   U is N or C,    -   and wherein at most four of the groups V, T, U, Z, Y, X and W        are N,    -   and at least one of the groups T, U, Y, X and W is N,    -   or anyone of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

According to one aspect, formula (I) as defined above includes acompound wherein Z is N, V is C, Y is N, X is C, T is C, U is C and W isC, which can be used as an agent for preventing, inhibiting or treatingcancer.

According to another aspect, formula (I) as defined above includes acompound wherein Z is C, V is C, Y is N, X is C, T is C, U is C and W isC, which can be used as an agent for preventing, inhibiting or treatingcancer.

According to another aspect, formula (I) as defined above includes acompound wherein Z is N, V is C, Y is C, X is N, T is C, U is C and W isC, which can be used as an agent for preventing, inhibiting or treatingcancer.

According to another aspect, formula (I) as defined above includes acompound wherein Z is N, V is C, Y is C, X is C, T is C, U is C and W isN, which can be used as an agent for preventing, inhibiting or treatingcancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is N and is in the para position withrespect to Z, Y is N, X is C, T is C, U is C and W is C, which can beused as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is N and is in the para position withrespect to Z, Y is C, X is N, T is C, U is C and W is C, which can beused as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is N and is in the meta position withrespect to Z and is in the para position with respect to the bond linkedto NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agentfor preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is N and is in the meta position withrespect to Z and is in the para position with respect to the bond linkedto NR″, Y is C, X is N, T is C, U is C and W is C, for use as an agentfor preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is C, Y is C, X is N, T is C, U is C and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is C, Y is N, X is N, T is C, U is C and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is N and is in the meta position withrespect to Z and in the ortho position with respect to the bond linkedto NR″, Y is N, X is C, T is C, U is C and W is C, for use as an agentfor preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is N and is in the para position withrespect to Z, Y is C, X is C, T is C, U is C and W is N, for use as anagent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is N and is in the para position withrespect to Z, Y is C, X is N, T is C, U is C and W is C, for use as anagent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is C, Y is N, X is N, T is C, U is C and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is N and is in the meta position withrespect to Z and is in the ortho position with respect to the bondlinked to NR″, Y is N, X is N, T is C, U is C and W is C, for use as anagent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is C, V is C, Y is C, X is C, T is N, U is C and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is C, Y is C, X is C, T is N, U is C and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to another aspect, formula (I) as defined above includes acompound, wherein Z is N, V is C, Y is C, X is C, T is C, U is N and Wis C, for use as an agent for preventing, inhibiting or treating cancer.

According to one preferred aspect, formula (I) as defined above, whereinZ is N, V is C, Y is N, X is C, T is C, U is C and W is C, for use as anagent for preventing, inhibiting or treating cancer.

According to another preferred aspect, formula (I) as defined aboveincludes a compound, wherein Z is N, V is N and is in the para positionwith respect to Z, Y is N, X is C, T is C, U is C and W is C, for use asan agent for preventing, inhibiting or treating cancer.

According to another preferred aspect, formula (I) as defined aboveincludes a compound, wherein Z is C, V is C, Y is C, X is C, T is N, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating cancer.

According to another preferred aspect, formula (I) as defined aboveincludes a compound, wherein Z is N, V is C, Y is C, X is C, T is C, Uis N and W is C, for use as an agent for preventing, inhibiting ortreating cancer.

The compounds described herein may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

The compounds of formula (I) can include physiologically acceptable acidaddition salts such as hydrobromide, tartrate, citrate,trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate,mesylate, formate, acetate and fumarate.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the compounds describe herein can include all suchsolvates.

In the context of EMBODIMENT I of the present disclosure, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃        normal, secondary or tertiary saturated hydrocarbon. Examples        are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,    -   “(C₁-C₃)alkoxy” as used herein respectively refers to        O—(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.        Examples include, but are not limited to, methoxy, ethoxy,        1-propoxy, 2-propoxy,    -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively        to alkyl group and alkoxy group as above-defined, the groups        being substituted by at least one fluorine atom. Examples of        perfluoroalkyl groups include, but are not limited to,        trifluoromethyl or perfluoropropyl.    -   “patient” may extend to humans or mammals. For example, the term        “patient” can include cats or dogs.

In one aspect, the compounds described herein include a compound offormula (Ia)

-   -   wherein:    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl        group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group,        a —NR₁R₂ group and a (C₁-C₃)alkoxy group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom, a halogen atom or a group chosen among a        (C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a        —NR₁R₂ group,    -   R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ib)

-   -   wherein:    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a        (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a phenoxy group and a        (C₁-C₄)alkoxy group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is preferably 1 or 2,    -   n′ is as defined above and is preferably 1,    -   R′ is a hydrogen atom, a halogen atom or a group chosen among a        (C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ic)

-   -   wherein:    -   R independently represent a hydrogen atom or a group chosen        among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂        group, a —COOR₁ group, a —NO₂ group and a (C₁-C₃)alkoxy group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Id)

-   -   wherein:    -   R independently represents a hydrogen atom or a group chosen        among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a        (C₁-C₃)alkoxy group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In certain aspects, the compounds described herein include a compound offormula (Ie)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom, a halogen atom or a group chosen among a        (C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In another aspect, the compounds described herein include a compound offormula (If)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ig)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom or a halogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ih)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ii)

-   -   wherein:    -   R independently represents a hydrogen atom or a group chosen        among a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ij)

-   -   wherein:    -   R independently represents a hydrogen atom or a group chosen        among a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ik)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Il)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Im)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Io)

-   -   wherein:    -   R independently represent a hydrogen atom or a halogen atom or a        group chosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl        group, said alkyl being optionally mono-substituted by a        hydroxyl group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl        group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ip)

-   -   wherein:    -   R represents a hydrogen atom,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Iq)

-   -   wherein:    -   R independently represents a hydrogen atom, a (C₁-C₃)alkoxy        group or a (C₁-C₃)fluoroalkoxy group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, a        N-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a        morpholino group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Ir)

-   -   wherein:    -   R independently represents a hydrogen atom or a (C₁-C₃)alkyl        group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 1,    -   R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, a        morpholino group and a (C₁-C₃)alkoxy group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In one aspect, the compounds described herein include a compound offormula (Iee)

-   -   wherein:    -   R independently represents a hydrogen atom, a (C₁-C₃)alkyl group        or a (C₁-C₃)fluoroalkyl group,    -   R″ is as defined above and is advantageously a hydrogen atom,    -   n is as defined above and is advantageously 1,    -   n′ is as defined above and is advantageously 2,    -   R′ is a hydrogen atom or a (C₁-C₃)alkyl group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

Among the previous defined families of compounds of formulae (Ia) to(Iee), some are more particularly preferred for their use as an agentfor preventing, inhibiting or treating cancer. These preferred compoundsparticularly belong to formulae (Ia), (Ie), (Iq) and (Iee), as definedabove or one of its pharmaceutically acceptable salts.

Accordingly, the portions below further relate to a compound chosenamong compounds of formulae (Ia), (Ie), (Iq) and (Iee), and theirpharmaceutically acceptable salts for use as an agent for preventing,inhibiting or treating cancer.

In certain aspects, the compounds described herein include a compound offormula (Ia)

-   -   wherein:    -   R independently represents a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a —COOR₁        group and a (C₁-C₃)fluoroalkyl group,    -   R″ is as defined above and more preferably is a hydrogen atom,    -   R₁ is as defined above,    -   n is as defined above,    -   n′ is as defined above,    -   R′ is a halogen atom, a (C₁-C₄)alkyl group, a (C₁-C₄)alkoxy        group or a —NO₂ group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In certain aspects, the compounds described herein include a compound offormula (Ie)

-   -   wherein:    -   R represents a hydrogen atom or a (C₁-C₄)alkyl group,    -   R″ is as defined above and more preferably is a hydrogen atom,    -   n is as defined above,    -   n′ is as defined above,    -   R′ is a halogen atom,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In certain aspects, the compounds described herein include a compound offormula (Iq)

-   -   wherein:    -   R′, R″, n and n′ are as defined in formula (I), and    -   R is a (C₁-C₃)fluoroalkoxy group,    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In certain aspects, the compounds described herein include a compound offormula (Iee)

-   -   wherein:    -   R is independently a hydrogen atom or a (C₁-C₄)alkyl group,    -   R′, R″, n and n′ are as defined in formula (I),    -   or one of its pharmaceutically acceptable salt,    -   for use as an agent for preventing, inhibiting or treating        cancer.

In certain aspects, the compounds described herein include a compound offormula (Ia) or (Ie) as defined above or one of its pharmaceuticallyacceptable salts, for use as an agent for preventing, inhibiting ortreating cancer.

According to a preferred embodiment, the compounds described herein foruse as an agent for preventing, inhibiting or treating cancer, is chosenfrom:

-   -   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine    -   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid    -   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine    -   (4) Pyridin-2-yl-quinolin-2-yl-amine    -   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid    -   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine    -   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile    -   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine    -   (9) Pyridin-2-yl-quinolin-3-yl-amine    -   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine    -   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine    -   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine    -   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid    -   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine    -   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile    -   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (33) 2-(quinolin-2-ylamino)isonicotinonitrile    -   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (37)        8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine    -   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile    -   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid    -   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (47) 5-cyano-2-(quinolin-2-yl amino)pyridin-1-ium chloride    -   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium        chloride    -   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine    -   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine    -   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile    -   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine    -   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine    -   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine    -   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (59) methyl 6-(quinolin-2-yl amino)nicotinate    -   (60) methyl        6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (61) methyl        6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (62) methyl        2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine    -   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-di amine    -   (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine    -   (67) methyl        6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (68)        8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol    -   (70)        8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine    -   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine    -   (74)        3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (75)        4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (76) N-(4-methoxyphenyl)quinolin-2-amine    -   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine    -   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine    -   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (81)        1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine    -   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (85) N-(4-nitrophenyl)quinolin-2-amine    -   (86) N-(3-fluorophenyl)quinolin-2-amine    -   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine    -   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (91)        3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (94)        8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (95)        3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine    -   (97)        4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine    -   (102) N-(4-phenoxyphenyl)quinolin-2-amine    -   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (104)        8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine    -   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine    -   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine    -   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine    -   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine    -   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (113) N-(pyrazin-2-yl)quinolin-2-amine    -   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine    -   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine    -   (118) N-(pyridin-3-yl)quinolin-3-amine    -   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine    -   (120) N-(pyridin-4-yl)quinolin-2-amine    -   (121) N-(pyridin-4-yl)quinolin-3-amine    -   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine    -   (123) N-(4-methoxyphenyl)quinolin-3-amine    -   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (128) N-(pyrimidin-2-yl)quinolin-2-amine    -   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine    -   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine    -   (131) N-(pyrazin-2-yl)quinolin-6-amine    -   (132) N-(pyrazin-2-yl)quinolin-3-amine    -   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine    -   (134) N-(naphthalen-2-yl)pyridin-2-amine    -   (135) N-(pyridin-2-yl)quinoxalin-2-amine    -   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile    -   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine    -   (139)        N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine    -   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine    -   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine    -   (143)        4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine    -   (144)        4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine    -   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine    -   (147)        4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine    -   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine    -   (149)        5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine    -   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine    -   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (153)        6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine    -   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine    -   (156)        4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine    -   (158)        N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine    -   (159) N-(3-aminopyridin-2-yl)quinolin-3-amine    -   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine    -   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine    -   (164) [2-(quinoxalin-2-yl amino)pyridin-4-yl]methanol    -   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine    -   (166)        N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine    -   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (168)        N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine    -   and their pharmaceutically acceptable salts.

Among the compounds described above, compounds (6), (18), (30), (35),(36), (37), (45), (48), (51), (52), (53), (55), (56), (58), (61), (63),(64), (109), (110), (112), (143), (144) and (148) are of particularinterest.

As discussed above, the compounds described herein include compound (6),(18), (30), (35), (36), (37), (45), (48), (51), (52), (53), (55), (56),(58), (61), (63), (64), (109), (110), (112), (143), (144) and (148) orone of its pharmaceutically acceptable salts for use as an agent forpreventing, inhibiting or treating cancer.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) and (Iee) cancomprise one or more asymmetric carbon atoms. They can thus exist in theform of enantiomers or of diastereoisomers. These enantiomers,diastereoisomers and their mixtures, including the racemic mixtures, areencompassed within the scope of the present invention.

The compound of formula (I) and the derivatives thereof can includetheir pharmaceutically acceptable salts, which include hydrobromide,tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate,triflate, maleate, mesylate, formate, acetate and fumarate.

In certain aspects, the compounds described herein includes compounds offormula (Ig)

-   -   wherein:    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl        group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a        (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a        (C₁-C₃)alkoxy group,    -   n is 1 or 2,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   with the proviso that R and R′ are not simultaneously a hydrogen        atom,    -   and when n and n′ are 1 and R is a hydrogen atom then R′ is not        a —COOH group,    -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds offormula (If)

-   -   wherein:    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl        group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a        (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a        (C₁-C₃)alkoxy group,    -   n is 1 or 2,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds offormula (Ih)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

-   -   n is 1 or 2,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds offormula (Il)

-   -   wherein:    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl        group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a        (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a —NR₁R₂ group, and a        (C₁-C₃)alkoxy group,    -   n is 1 or 2,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   with the proviso that R and R′ are not simultaneously a hydrogen        atom,    -   or anyone of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds offormula (Im)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

-   -   n is 1 or 2,    -   n′ is 1 or 2,    -   R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl        group, a halogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂        group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group and a —CN group,    -   R″ is a hydrogen atom or a (C₁-C₄)alkyl group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   with the proviso that when n and n′ are 1 and R is a hydrogen        atom, R′ is not a chlorine atom,    -   or anyone of its pharmaceutically acceptable salt.

For simplification, the following compounds and their correspondingdefinitions are called “new compounds”.

In certain aspects, the compounds described herein includes compounds offormula (Ia), as such,

-   -   wherein:    -   R″ and n are as defined in formula (Ia),    -   n′ is 1,    -   R independently represent a hydrogen atom, a halogen atom or a        group chosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl        group, a —COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group,        a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,    -   R′ is a hydrogen atom or a halogen atom or a group chosen among        a (C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,    -   R₁ is a hydrogen atom or a (C₁-C₃)alkyl group:    -   with the proviso that    -   when R and R′ are not simultaneously a hydrogen atom,    -   when n is 1, R is not a methyl group in the ortho or para        positions with respect to Z, Z being N,    -   when R′ is a hydrogen atom, R is not a bromine atom or a        chlorine atom,    -   when R is a hydrogen atom, R′ is not a methyl or ethyl group, a        —COOH group, a COOC₂H₅ group or a bromine atom, said bromine        atom being in the ortho position with respect to the bond linked        to NR″,    -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia), as such,wherein,

-   -   R independently represents a hydrogen atom or a (C₁-C₃) alkyl        group,    -   R″ is as defined in formula (Ia),    -   R′ is a hydrogen atom, a halogen atom, a (C₁-C₃)alkoxy group or        a —NO₂ group,    -   n′ is 1,    -   n is 1,    -   with the proviso that    -   when n is 1, R is not a methyl group in the ortho or para        positions with respect to Z, Z being N,    -   or one of its pharmaceutically acceptable salt.

In this aspect the compounds described herein can include compounds offormula (Ia′), as such,

-   -   wherein,    -   R independently represents a hydrogen atom, a (C₁-C₃) alkyl        group, a (C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl        group,    -   R″ is as defined in formula (Ia),    -   n is 1 or 2,    -   or one of its pharmaceutically acceptable salt.

In certain aspects, the compounds described herein includes compounds offormula (Ie)

-   -   wherein:    -   R, R′, R″ n and n′ are as defined in formula (I),    -   with the proviso that    -   when R is a hydrogen atom, R′ is not a bromine atom,    -   or one of its pharmaceutically acceptable salt.

The compounds described herein further relate to a compound of formula(Iq) as defined above, as such

-   -   wherein:    -   R, R′, R″ and n′ are as defined in formula (I),    -   n is 1 or 2,    -   with the proviso that    -   R′ and R are not simultaneously a hydrogen atom,    -   when R′ is a hydrogen atom, R is not a —NO₂ group or a —NH₂        group,    -   when n is 2 and R′ is a hydrogen atom, R is not a COOC₂H₅ group        or a chlorine atom,    -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds describedherein include compounds of formula (Iq), as such, wherein

-   -   R′, R″, n and n′ are as defined in formula (I), and    -   R is a (C₁-C₃)fluoroalkoxy group,    -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds describedherein include compounds of formula (Iq), as such, wherein

-   -   R, R″, n and n′ are as defined in formula (I), and    -   R′ is a —NR₁R₂ group,    -   R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl        group,    -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the compounds describedherein include compounds of formula (Iq), as such, wherein

-   -   R, R″, n and n′ are as defined in formula (I), and    -   R′ is a morpholinyl group, a morpholino group or a        N-methylpiperazinyl group,    -   or one of its pharmaceutically acceptable salt.

In a further aspect, the compounds described herein includes a compoundof formula (Iee) as defined above, as such

-   -   wherein:    -   R, R′, R″, n and n′ are as defined in formula (I),    -   or one of its pharmaceutically acceptable salt,    -   with the exclusion of the following compound

-   -   and with the exclusion of compounds wherein R is a —NO₂ group or        a —NH₂ group when R′ is a hydrogen or a methyl group.

Still according to this particular embodiment, the compounds describedherein include compounds of formula (Iee), as such, wherein

-   -   R′, R″, n and n′ are as defined in formula (I), and    -   R is a (C₁-C₃)fluoroalkyl group,    -   or one of its pharmaceutically acceptable salt.

Among the compounds discussed above, compounds (1), (2), (5)-(8),(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121),(124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and theirpharmaceutically acceptable salts are of particular interest.

As discussed above, the compounds described herein include compounds(1), (2), (5)-(8), (10)-(16), (18), (21)-(44), (46)-(75), (77)-(84),(86)-(119), (121), (124)-(130), (132), (135)-(141), (143)-(147),(149)-(168) and their pharmaceutically acceptable salts, as such.

More preferably, compounds (143), (144), (149), (166), (167) and theirpharmaceutically acceptable salts are of particular interest.

For example, the compounds described herein can include compounds (143),(144), (149), (166), (167) and their pharmaceutically acceptable salts,where the pharmaceutically acceptable salts include, but are not limitedto, hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate.

In certain aspects, the compounds described herein include compounds(143) and (144) and their pharmaceutically acceptable salts, whichinclude, but are not limited to, hydrobromide, tartrate, citrate,trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate, maleate,mesylate, formate, acetate and fumarate.

The compounds described herein, e.g. compounds of formulae (Ia), (Ie),(Iq) and (Iee) and the specific compounds as listed above, are not onlyuseful as agent for inhibiting, preventing or treating cancer but canalso be useful for inhibiting, preventing or treating premature aging orprogeria and for inhibiting, preventing or treating AIDS.

According to an aspect of the invention, the compounds may be useful toinhibit, prevent and/or treat diseases with premature aging and that arelikely related to aberrant splicing of the nuclear lamin A gene. Forexample, such diseases may include Hutchinson Guilford Progeria Syndrome(HGPS), progeria, premature aging associated with HIV infection,muscular dystrophy, Charcot-Marie-Tooth disorder, Werner syndrome, butthe diseases may also include atherosclerosis, insulin resistant type IIdiabetes, cataracts, osteoporosis and aging of the skin such asrestrictive dermopathy.

The compounds described herein can be prepared by conventional methodsof organic synthesis practiced by those skilled in the art. The generalreaction sequences outlined below represent a general method useful forpreparing the compounds of the present invention and are not meant to belimiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 below.

As appears in the scheme, two routes are available for recovering acompound of formula (I) according to the present invention.

The synthesis is based on a coupling reaction alternatively startingfrom a halogeno-bicycle of formula (III), wherein X, Y, W, T, U, n′, R′and R″ are as defined above and X′ is a chlorine atom or a bromine atomor from a chloro-monocycle of formula (V), wherein Z, V, n and R are asdefined above and X is a chlorine atom or a bromine atom.

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a molar ratio ranging from 1 to 1.5 with respect to thecompound of formula (III) in presence of an inorganic base, such asCs₂CO₃ or K₂CO₃ in a molar ratio ranging from 1 and 2, in the presenceof a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or X-Phos(2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in an amountranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (III), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % to 10 mol %relative to the total amount of compound of formula (III). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

According to route (B) the compound of formula (V) is placed in a proticsolvent such as tert-butanol. The compound of formula (VI) is then addedin a molar ratio ranging from 1 to 1.5 with respect to the compound offormula (V) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃ ina molar ratio ranging from 1 to 2, in the presence of a diphosphine,such as Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) orX-Phos (2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) in anamount ranging from 2 mol % to 10 mol % relative to the total amount ofcompound of formula (V), and in the presence of a catalyst, such asPd(OAc)₂ or Pd₂dba₃ in an amount ranging from 2 mol % to 10 mol %relative to the total amount of compound of formula (V). The reactionmixture can then be heated at a temperature ranging from 80 to 120° C.,for example at 90° C. and stirred for a time ranging form 15 to 25hours, for example during 20 hours under inert gas and for exampleargon. The reaction mixture can be concentrated under reduced pressure.

The starting compounds of formula (III), (IV), (V) and (VI) arecommercially available or can be prepared according to methods known tothe person skilled in the art. The chemical structures and spectroscopicdata of some compounds of formula (I) are illustrated respectively inthe following Table I and Table II.

TABLE I (I)

Formula (IAa) 1

2

3

4

5

6

7

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

150

151

152

153

154

Formula (Ib) 8

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

155

156

157

158

Formula (Ic) 9

10

11

12

13

14

105

106

159

Formula (Id) 15

16

107

108

Formula (Ie) 109

110

111

112

113

114

115

116

117

Formula (If) 118

Formula (Ig) 119

120

Formula (Ih) 121

Formula (Ii) 122

123

Formula (Ij) 124

125

126

127

Formula (Ik) 128

129

130

Formula (Il) 131

Formula (Im) 132

Formula (Io) 135

136

137

138

139

140

141

160

161

162

163

164

165

Formula (Ip) 142

Formula (Iq) 143

144

166

167

Formula (Ir) 145

146

147

168

Formula (Iee) 148

149

TABLE II Ex Characterizations 1 MS (ESI) [M + H]⁺ = 256 2 ¹H NMR (300MHz, D₂O) δ 8.31 (d, J = 5.1, 1H), 8.21 (d, J = 9.3, 1H), 7.60 (d, J =7.5, 3H), 7.34 (dd, J = 6.2, 15.6, 2H), 7.18 (s, 1H), 6.99 (d, J = 9.1,1H) MS (ESI) [M + H]⁺ = 266 5 MS (ESI) [M + H]⁺ = 300 6 ¹H NMR (300 MHz,DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 8.8, 2H), 7.78 (dd, J= 7.7, 13.7, 2H), 7.46 (d, J = 8.9, 1H), 7.31 (t, J = 7.8, 1H), 6.86 (d,J = 4.3, 1H), 2.37 (s, 3H). ¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61,148.37, 147.32, 142.65, 137.52, 129.68, 129.47, 126.82, 125.06, 123.26,118.36, 115.10, 113.31, 21.24. MS (ESI) [M + H]⁺ = 270 7 ¹H NMR (300MHz, DMSO) δ 10.71 (s, 1H), 8.71 (d, J = 1.4, 1H), 8.62 (d, J = 8.9,1H), 8.24 (d, J = 8.9, 1H), 8.17 (dd, J = 1.9, 8.9, 1H), 7.89-7.74 (m,2H), 7.66 (dd, J = 7.9, 14.2, 2H), 7.42 (t, J = 7.3, 1H). ¹³C NMR (75MHz, DMSO) δ 156.09, 152.40, 152.11, 146.24, 141.07, 137.83, 129.87,127.67, 126.78, 124.50, 124.21, 118.04, 114.49, 111.67, 100.12. MS (ESI)[M + H]⁺ = 247 8 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9, 1H), 7.79(d, J = 8.4, 1H), 7.65 (t, J = 7.7, 3H), 7.59 (dd, J = 7.1, 8.3, 1H),7.31 (t, J = 7.0, 1H), 7.20 (d, J = 8.5, 2H), 6.88 (d, J = 8.9, 1H),6.80 (s, 1H) ¹³C NMR (75 MHz, CDCl₃) δ 153.88, 147.62, 144.35, 139.26,138.11, 130.13, 127.65, 127.12, 124.43, 123.70, 122.20, 120.95, 112.25.MS (ESI) [M + H]⁺ = 305 10 ¹H NMR (300 MHz, CDCl₃) δ 9.10 (d, J = 2.5,1H), 8.83 (d, J = 2.6, 1H), 8.02 (d, J = 7.9, 1H), 7.94 (dd, J = 1.3,5.0, 1H), 7.85-7.79 (m, 1H), 7.52 (pd, J = 1.5, 6.9, 2H), 7.33 (s, 1H),7.04 (dd, J = 1.2, 7.9, 1H), 6.81 (dd, J = 5.1, 7.9, 1H), 3.95 (s, 3H)11 MS (ESI) [M + H]⁺ = 290 12 ¹H NMR (300 MHz, CDCl₃) δ 9.18 (d, J =2.7, 1H), 8.86 (d, J = 2.5, 1H), 8.56 (d, J = 2.3, 1H), 8.33 (dd, J =2.7, 9.2, 1H), 8.08 (d, J = 8.5, 1H), 7.83 (d, J = 8.5, 1H), 7.71-7.63(m, 2H), 7.57 (t, J = 7.4, 2H), 6.82 (d, J = 9.1, 1H) 13 ¹H NMR (300MHz, CDCl₃) δ 8.83 (d, J = 2.6, 1H), 8.37 (d, J = 2.3, 1H), 8.00 (d, J =8.2, 1H), 7.71 (d, J = 7.7, 1H), 7.59-7.51 (m, 1H), 7.46 (dd, J = 7.3,15.1, 2H), 6.71 (d, J = 8.3, 1H), 6.67 (d, J = 7.4, 1H), 2.49 (s, 3H)¹³C NMR (75 MHz, CDCl₃) δ 157.13, 154.59, 145.81, 144.43, 138.78,134.54, 129.22, 128.86, 127.41, 127.27, 121.48, 115.41, 106.50, 24.18.MS (ESI) [M + H]⁺ = 236 14 MS (ESI) [M + H]⁺ = 266 15 MS (ESI) [M + H]⁺= 290 16 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5, 4.2, 1H), 8.04(dd, J = 4.7, 8.7, 2H), 7.92 (d, J = 2.4, 1H), 7.59 (dd, J = 2.5, 9.1,1H), 7.47 (t, J = 7.8, 1H), 7.35 (dd, J = 4.2, 8.3, 1H), 6.87 (s, 1H),6.81 (d, J = 8.2, 1H), 6.70 (d, J = 7.4, 1H), 2.50 (s, 3H) MS (ESI) [M +H]⁺ = 236 18 ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J = 59.9, 2H), 7.76 (d,J = 8.6, 1H), 7.58 (t, J = 8.3, 2H), 7.42 (d, J = 7.8, 1H), 7.09 (t, J =7.7, 1H), 6.95 (d, J = 8.7, 1H), 6.71 (d, J = 7.3, 1H), 2.38 (s, 3H) 21¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.13 (d, J = 5.1, 1H), 7.89 (d,J = 8.3, 1H), 7.79 (s, 1H), 7.63 (d, J = 8.0, 1H), 7.56 (d, J = 7.3,1H), 7.38 (s, 1H), 7.33 (t, J = 7.5, 1H), 6.79 (d, J = 4.9, 1H), 2.44(s, 6H) 22 ¹H NMR (300 MHz, CDCl₃) δ 8.95 (d, J = 8.4, 1H), 8.28 (d, J =5.7, 1H), 7.87 (d, J = 8.3, 1H), 7.78 (s, 1H), 7.76-7.70 (m, 1H), 7.62(d, J = 8.0, 1H), 7.60-7.52 (m, 1H), 7.42 (s, 1H), 7.32 (t, J = 7.4,1H), 6.95 (dd, J = 5.1, 6.5, 1H), 2.45 (s, 3H) 23 ¹H NMR (300 MHz,CDCl₃) δ 8.64 (d, J = 8.4, 1H), 8.55 (d, J = 2.1, 1H), 8.03 (s, 1H),7.90 (d, J = 8.5, 4H), 7.66 (t, J = 7.6, 1H), 7.44 (t, J = 7.6, 1H),7.06 (s, 1H), 2.67 (s, 4H) 24 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (d, J =8.9, 1H), 8.53 (d, J = 1.7, 1H), 7.94 (dd, J = 2.2, 8.9, 1H), 7.92-7.84(m, 2H), 7.67 (d, J = 8.6, 2H), 7.65-7.58 (m, 1H), 7.40 (t, J = 7.4,1H), 2.49 (s, 3H) 25 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 5.2, 1H),8.10 (s, 1H), 7.90 (d, J = 8.8, 1H), 7.79 (d, J = 9.0, 1H), 7.66 (d, J =2.2, 1H), 7.55 (dd, J = 2.3, 8.9, 1H), 7.39 (d, J = 9.0, 1H), 6.79 (d, J= 5.2, 1H), 2.42 (s, 3H) MS (ESI) [M + H]⁺ = 270 26 ¹H NMR (300 MHz,CDCl₃) δ 8.06 (d, J = 8.3, 1H), 7.70 (d, J = 9.0, 1H), 7.64 (d, J = 8.9,1H), 7.49 (t, J = 7.9, 2H), 7.40 (dd, J = 2.3, 8.9, 1H), 7.18 (d, J =8.9, 1H), 6.68 (d, J = 7.4, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 270 27¹H NMR (300 MHz, CDCl₃) δ 9.17 (d, J = 2.5, 1H), 8.71 (s, 1H), 8.49 (dd,J = 2.6, 9.0, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9, 2H), 7.74-7.64 (m,1H), 7.48 (dd, J = 4.2, 11.4, 1H), 7.09 (s, 1H), 2.71 (s, 3H) 28 ¹H NMR(300 MHz, CDCl₃) δ 8.64-8.51 (m, 3H), 8.18 (d, J = 9.0, 1H), 7.93 (d, J= 8.4, 1H), 7.79 (d, J = 8.1, 1H), 7.73-7.64 (m, 1H), 7.51-7.41 (m, 1H),7.00 (dd, J = 4.6, 8.2, 1H), 6.75 (dd, J = 4.6, 8.3, 0H) 29 ¹H NMR (300MHz, CDCl₃) δ 10.77 (s, 1H), 8.60 (s, 3H), 8.19 (d, J = 8.2, 1H), 7.76(dd, J = 6.6, 25.5, 2H), 7.38 (d, J = 7.2, 1H), 7.04 (d, J = 4.4, 1H) 30¹H NMR (300 MHz, CDCl₃) δ 8.46 (dd, J = 1.9, 5.0, 1H), 7.87 (dd, J =2.0, 7.6, 1H), 7.82 (d, J = 7.3, 1H), 7.60 (t, J = 7.3, 2H), 7.43-7.33(m, 1H), 6.90 (dd, J = 5.0, 7.6, 1H), 2.64 (s, 3H) 31 ¹H NMR (300 MHz,CDCl₃) δ 8.44 (d, J = 9.1, 1H), 8.17 (d, J = 4.8, 1H), 8.03 (d, J = 9.1,1H), 7.78 (d, J = 8.4, 1H), 7.68 (d, J = 8.0, 1H), 7.62-7.54 (m, 1H),7.39 (d, J = 7.3, 1H), 7.32 (t, J = 7.5, 1H), 6.82 (dd, J = 5.0, 7.3,1H), 2.31 (s, 3H) MS (ESI) [M + H]⁺ = 236 32 ¹H NMR (300 MHz, CDCl₃) δ8.23 (d, J = 8.5, 1H), 8.10 (s, 1H), 7.91 (d, J = 8.9, 1H), 7.82 (d, J =8.4, 1H), 7.62 (d, J = 8.3, 1H), 7.56 (d, J = 7.3, 1H), 7.50 (dd, J =1.8, 8.5, 1H), 7.37-7.24 (m, 2H), 2.26 (s, 3H) MS (ESI) [M + H]⁺ = 23633 ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s, 1H), 8.32 (d, J = 5.0, 1H), 7.95(d, J = 8.8, 1H), 7.84 (d, J = 8.3, 1H), 7.60 (dd, J = 7.4, 14.1, 2H),7.32 (t, J = 7.5, 1H), 7.04 (dd, J = 5.0, 9.0, 2H) MS (ESI) [M + H]⁺ =247 34 ¹H NMR (300 MHz, CDCl₃) δ 8.52 (s, 1H), 8.45 (d, J = 8.6, 1H),8.01 (d, J = 8.8, 1H), 7.87 (dd, J = 2.5, 8.5, 2H), 7.72-7.56 (m, 2H),7.39 (d, J = 9.0, 2H) MS (ESI) [M + H]⁺ = 290 35 ¹H NMR (300 MHz, CDCl₃)δ 8.32 (d, J = 9.1, 1H), 8.07 (d, J = 4.8, 1H), 7.93 (d, J = 9.1, 1H),7.59 (t, J = 7.9, 1H), 7.52 (d, J = 8.0, 1H), 7.36 (d, J = 7.2, 1H),7.14 (t, J = 7.8, 1H), 6.77 (dd, J = 5.0, 7.3, 1H), 2.29 (s, 3H) MS(ESI) [M + H]⁺ = 270 36 ¹H NMR (300 MHz, CDCl₃) δ 8.70 (d, J = 7.2, 1H),8.01 (s, 1H), 7.82 (d, J = 8.9, 1H), 7.62 (d, J = 7.6, 1H), 7.53 (dd, J= 1.8, 8.6, 1H), 7.46 (d, J = 7.9, 1H), 7.12 (t, J = 7.8, 1H), 7.05 (d,J = 8.8, 1H), 2.21 (s, 3H) MS (ESI) [M + H]⁺ = 270 37 ¹H NMR (300 MHz,CDCl₃) δ 9.08 (d, J = 8.5, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.02 (d, J =8.1, 2H), 7.77 (d, J = 7.2, 1H), 7.62 (d, J = 7.6, 1H), 7.35-7.24 (m,1H), 7.12 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 324 38 ¹H NMR (300 MHz,CDCl₃) δ 8.69 (d, J = 9.1, 1H), 7.97 (d, J = 9.1, 1H), 7.80-7.74 (m,1H), 7.70 (d, J = 8.4, 1H), 7.59 (d, J = 8.0, 1H), 7.54-7.45 (m, 1H),7.22 (t, J = 7.5, 1H), 6.87 (d, J = 7.9, 1H), 6.68 (dd, J = 5.0, 7.9,1H), 3.73 (s, 3H) MS (ESI) [M + H]⁺ = 252 39 ¹H NMR (300 MHz, CDCl₃) δ8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J = 6.7, 2H),7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J = 8.8, 1H),6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t, J = 7.7,3H) 40 ¹H NMR (300 MHz, DMSO) δ 9.75 (s, 1H), 9.12 (d, J = 2.3, 1H),8.50 (d, J = 2.2, 1H), 8.48 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.80(s, 1H), 7.64 (t, J = 7.7, 1H), 7.45 (t, J = 7.8, 1H) 41 ¹H NMR (300MHz, CDCl₃) δ 8.52 (dd, J = 2.8, 8.6, 1H), 8.35 (s, 1H), 8.15 (d, J =2.3, 1H), 7.94 (d, J = 8.8, 1H), 7.84 (d, J = 8.2, 1H), 7.65 (d, J =7.8, 1H), 7.59 (d, J = 7.2, 1H), 7.50-7.40 (m, 1H), 7.33 (t, J = 7.4,1H), 7.11 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 240 42 ¹H NMR (300 MHz,CDCl₃) δ 8.55 (d, J = 6.8, 1H), 8.01 (d, J = 8.9, 2H), 7.82 (dd, J =9.1, 17.3, 2H), 7.69 (d, J = 8.0, 1H), 7.63 (t, J = 7.6, 1H), 7.37 (t, J= 7.5, 1H), 7.32-7.18 (m, 2H) MS (ESI) [M + H]⁺ = 290 43 ¹H NMR (300MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J = 4.1, 9.3, 1H), 8.31 (d, J =2.9, 1H), 8.20 (d, J = 8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J = 8.9,1H), 7.32 (t, J = 7.8, 1H) ¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32,153.04, 150.17, 142.55, 137.73, 135.06, 134.74, 129.58, 129.49, 126.86,125.29, 125.14, 125.04, 123.36, 114.91, 113.36. MS (ESI) [M + H]⁺ = 27444 ¹H NMR (300 MHz, CDCl₃) δ 11.09 (s, 1H), 8.78 (d, J = 9.0, 1H), 8.42(dd, J = 1.9, 4.7, 1H), 8.28 (dd, J = 1.9, 7.8, 1H), 8.11 (d, J = 9.1,1H), 7.73 (d, J = 7.5, 1H), 7.65 (d, J = 8.1, 1H), 7.27 (dd, J = 6.4,9.2, 1H), 6.88 (dd, J = 4.8, 7.8, 1H) MS (ESI) [M + H]⁺ = 300 46 ¹H NMR(300 MHz, CDCl₃) δ 8.59 (d, J = 8.3, 1H), 7.73 (d, J = 8.3, 1H), 7.57(s, 1H), 7.51 (t, J = 7.9, 1H), 7.43 (t, J = 9.2, 2H), 7.17 (t, J = 7.4,1H), 6.67 (d, J = 7.4, 1H), 2.36 (s, 3H), 2.28 (s, 3H) 47 ¹H NMR (300MHz, MeOD) δ 8.99 (s, 1H), 8.76 (d, J = 9.2, 1H), 8.32 (d, J = 8.7, 1H),8.22 (d, J = 8.6, 1H), 8.11 (d, J = 7.8, 1H), 8.01 (t, J = 7.1, 1H),7.76 (t, J = 7.4, 1H), 7.55-7.43 (m, 2H) MS (ESI) [M + H]⁺ = 247 48 ¹HNMR (300 MHz, MeOD) δ 8.48 (d, J = 9.1, 1H), 8.40 (d, J = 6.7, 1H), 7.94(d, J = 8.4, 1H), 7.90 (d, J = 7.8, 1H), 7.54 (t, J = 8.0, 1H), 7.38 (d,J = 8.6, 1H), 7.30 (s, 2H), 2.58 (s, 3H) MS (ESI) [M + H]⁺ = 270 49 ¹HNMR (300 MHz, CDCl₃) δ 9.34 (s, 1H), 8.95 (s, 1H), 8.21 (d, J = 5.1,1H), 7.87 (d, J = 8.9, 1H), 7.71 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.19 (t, J = 7.8, 1H), 7.05 (d, J = 8.9, 1H), 6.84 (d, J = 5.1,1H), 2.76 (q, J = 7.6, 2H), 1.37 (t, J = 7.6, 3H) 50 ¹H NMR (300 MHz,CDCl₃) δ 8.57 (d, J = 29.4, 1H), 7.80 (d, J = 8.8, 1H), 7.66 (t, J =6.7, 2H), 7.46 (d, J = 7.9, 1H), 7.14 (t, J = 7.8, 1H), 7.06 (d, J =8.8, 1H), 6.79 (d, J = 7.3, 1H), 2.73 (dd, J = 7.6, 15.2, 2H), 1.28 (t,J = 7.7, 3H) 51 ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 8.06 (s, 1H),7.89 (d, J = 8.7, 1H), 7.71 (d, J = 7.4, 1H), 7.54 (d, J = 7.8, 1H),7.20 (t, J = 7.7, 1H), 7.02 (d, J = 8.8, 1H), 6.67 (s, 1H), 2.43 (s,3H), 2.39 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.15, 153.17, 152.82,150.16, 143.70, 137.92, 131.34, 129.89, 126.49, 125.47, 123.43, 118.62,114.47, 111.02, 24.13, 21.70. MS (ESI) [M + H]⁺ = 284 52 ¹H NMR (300MHz, CDCl₃) δ 8.89 (d, J = 8.8, 1H), 8.05 (d, J = 8.8, 1H), 8.01 (s,1H), 7.93 (d, J = 8.8, 1H), 7.79 (d, J = 7.5, 1H), 7.64 (d, J = 8.0,1H), 7.32 (t, J = 7.8, 1H), 7.13 (d, J = 8.8, 1H), 2.67 (s, 3H) 53 ¹HNMR (300 MHz, CDCl₃) δ 9.27 (s, 1H), 8.33 (d, J = 5.7, 1H), 8.13 (d, J =5.2, 1H), 8.00 (d, J = 8.8, 1H), 7.76 (d, J = 7.4, 1H), 7.60 (d, J =8.0, 1H), 7.29 (d, J = 7.9, 1H), 7.07 (d, J = 8.9, 1H), 6.97 (d, J =4.8, 1H) 54 MS (ESI) [M + H]⁺ = 250 55 ¹H NMR (300 MHz, CDCl₃) δ 8.19(s, 1H), 7.90 (d, J = 9.0, 1H), 7.63 (d, J = 7.5, 1H), 7.52 (d, J = 7.9,1H), 7.33 (d, J = 7.4, 1H), 7.14 (t, J = 7.8, 1H), 6.69 (d, J = 7.5,1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47 (s, 3H), 1.26 (t, J = 7.7, 3H)56 ¹H NMR (300 MHz, CDCl₃) δ 8.20 (s, 1H), 7.90 (d, J = 9.0, 1H), 7.63(d, J = 7.5, 1H), 7.52 (d, J = 7.9, 1H), 7.33 (d, J = 7.4, 1H), 7.14 (t,J = 7.8, 1H), 6.69 (d, J = 7.5, 1H), 2.70 (dd, J = 7.3, 14.8, 2H), 2.47(s, 3H), 1.25 (dd, J = 7.5, 15.5, 3H) 57 MS (ESI) [M + H]⁺ = 253 58 MS(ESI) [M + H]⁺ = 314-316 59 ¹H NMR (300 MHz, CDCl₃) δ 8.91 (d, J = 1.7,1H), 8.46 (d, J = 8.8, 1H), 8.28 (dd, J = 2.0, 8.8, 1H), 8.23 (s, 1H),8.03 (d, J = 8.8, 1H), 7.88 (d, J = 8.3, 1H), 7.70 (d, J = 8.0, 1H),7.67-7.58 (m, 1H), 7.38 (t, J = 7.4, 1H), 7.32 (d, J = 8.8, 2H), 3.91(s, 3H) 60 ¹H NMR (300 MHz, CDCl₃) δ 8.94 (d, J = 8.9, 1H), 8.91 (d, J =1.8, 1H), 8.37 (dd, J = 2.2, 8.8, 1H), 8.04 (d, J = 8.9, 2H), 7.77 (d, J= 7.5, 1H), 7.62 (d, J = 7.2, 1H), 7.30 (t, J = 7.8, 2H), 7.19 (d, J =8.8, 2H), 3.92 (s, 3H) 61 ¹H NMR (300 MHz, CDCl₃) δ 8.96 (d, J = 8.8,1H), 8.85 (d, J = 1.3, 1H), 8.28 (d, J = 9.9, 1H), 7.84 (d, J = 8.0,1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.4, 2H), 7.53 (d, J =8.4, 1H), 7.31 (t, J = 7.4, 1H), 3.88 (s, 4H), 2.42 (s, 4H) MS (ESI)[M + H]⁺ = 294 62 ¹H NMR (300 MHz, CDCl₃) δ 11.02 (s, 1H), 8.75 (d, J =9.2, 1H), 8.44 (d, J = 3.7, 1H), 8.31 (d, J = 7.9, 1H), 8.10 (d, J =9.0, 1H), 7.72 (d, J = 7.5, 1H), 7.64 (d, J = 8.2, 1H), 7.27 (d, J =8.1, 1H), 6.88 (dd, J = 4.7, 7.8, 1H), 3.97 (s, 3H) MS (ESI) [M + H]⁺ =314 63 MS (ESI) [M + H]⁺ = 266 64 ¹H NMR (300 MHz, DMSO) δ 10.38 (s,1H), 8.56 (s, 1H), 8.28 (d, J = 9.1, 1H), 8.20-8.03 (m, 3H), 7.50 (d, J= 8.7, 1H), 7.45 (d, J = 8.0, 1H), 6.88 (d, J = 4.4, 1H), 2.37 (s, 3H)65 MS (ESI) [M + H]⁺ = 314-316 66 MS (ESI) [M + H]⁺ = 250 67 ¹H NMR (300MHz, DMSO) δ 10.51 (s, 1H), 8.83 (d, J = 2.3, 1H), 8.62 (d, J = 9.3,1H), 8.24 (dd, J = 2.7, 9.1, 1H), 7.96 (d, J = 8.9, 1H), 7.81 (d, J =7.8, 1H), 7.67 (t, J = 7.6, 1H), 7.45 (d, J = 11.2, 2H), 3.86 (s, 3H),2.62 (s, 3H) MS (ESI) [M + H]⁺ = 294 68 ¹H NMR (300 MHz, CDCl₃) δ 9.57(s, 1H), 8.44 (d, J = 4.8, 1H), 8.05 (d, J = 8.8, 1H), 7.86 (s, 1H),7.80 (d, J = 7.5, 1H), 7.64 (d, J = 8.0, 1H), 7.31 (t, J = 7.8, 1H),7.19 (d, J = 4.3, 1H), 7.04 (d, J = 8.8, 1H) 69 ¹H NMR (300 MHz, CDCl₃)δ 9.12 (s, 1H), 7.94 (d, J = 8.6, 1H), 7.71 (d, J = 7.5, 1H), 7.57 (d, J= 7.8, 1H), 7.40 (s, 1H), 7.25 (d, J = 10.2, 2H), 7.17 (s, 1H), 7.05 (s,1H) 70 ¹H NMR (300 MHz, CDCl₃) δ 9.07 (d, J = 8.5, 1H), 7.97 (d, J =8.8, 1H), 7.90 (t, J = 8.0, 1H), 7.84 (s, 1H), 7.75 (dd, J = 1.1, 7.5,1H), 7.62-7.55 (m, 1H), 7.31 (d, J = 7.6, 1H), 7.27 (t, J = 7.8, 1H),7.08 (d, J = 8.8, 1H) MS (ESI) [M + H]⁺ = 274 71 MS (ESI) [M + H]⁺ = 27472 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J = 8.3,1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.57 (d, J = 7.9, 2H), 7.52 (d, J= 7.1, 1H), 7.28 (t, J = 7.4, 1H), 2.74 (q, J = 7.6, 2H), 2.42 (s, 3H),1.31 (t, J = 7.6, 3H) MS (ESI) [M + H]⁺ = 264 73 ¹H NMR (300 MHz, CDCl₃)δ 8.91 (dd, J = 3.8, 9.0, 1H), 8.11 (d, J = 2.9, 1H), 7.81 (d, J = 8.3,1H), 7.71 (s, 1H), 7.56 (dd, J = 7.4, 14.1, 2H), 7.51-7.42 (m, 1H), 7.29(d, J = 7.2, 1H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 254 74 ¹H NMR (300MHz, CDCl₃) δ 8.96 (d, J = 8.3, 1H), 8.49 (s, 1H), 7.89 (dd, J = 1.9,9.0, 1H), 7.82 (d, J = 8.2, 1H), 7.72 (s, 1H), 7.57 (t, J = 8.7, 3H),7.33 (t, J = 7.4, 1H), 2.37 (s, 3H) MS (ESI) [M + H]⁺ = 304 75 ¹H NMR(300 MHz, CDCl₃) δ 7.83 (d, J = 9.0, 1H), 7.69 (dd, J = 1.3, 7.6, 1H),7.53 (dd, J = 1.2, 8.0, 1H), 7.42 (d, J = 8.9, 2H), 7.15 (t, J = 7.8,1H), 6.89 (d, J = 8.9, 2H), 6.79 (d, J = 8.9, 2H), 2.97 (s, 6H) 77 ¹HNMR (300 MHz, CDCl₃) δ 7.83 (d, J = 8.8, 1H), 7.70 (d, J = 7.6, 1H),7.59 (d, J = 8.6, 2H), 7.52 (d, J = 7.3, 1H), 7.16 (t, J = 7.7, 1H),6.94 (d, J = 8.4, 3H), 6.86 (d, J = 8.8, 1H), 3.82 (s, 3H) ¹³C NMR (75MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96, 130.44, 129.99,126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74. MS (ESI) [M + H]⁺= 285 78 ¹H NMR (300 MHz, CDCl₃) δ 7.80 (t, J = 7.6, 2H), 7.64 (d, J =8.9, 2H), 7.61-7.55 (m, 1H), 7.33 (t, J = 7.6, 1H), 7.19 (d, J = 8.7,2H), 2.59 (s, 3H) 79 ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.4, 1H),7.76-7.71 (m, 2H), 7.69 (s, 1H), 7.57 (dd, J = 1.1, 8.0, 1H), 7.51 (ddd,J = 1.5, 7.0, 8.4, 1H), 7.29-7.21 (m, 1H), 6.96-6.90 (m, 2H), 3.82 (s,3H), 2.35 (s, 3H) 80 ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 8.9 Hz, 2H),7.84 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.57(t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H),6.53 (s, 1H), 2.42 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25,143.86, 139.33, 136.83, 128.93, 126.96, 126.71, 124.75, 123.56, 121.88,120.44, 119.95, 17.77. MS (ESI) [M + H]⁺ = 319 81 ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, J = 8.3, 1H), 7.66 (d, J = 8.5, 3H), 7.55 (d, J = 7.8,1H), 7.48 (t, J = 7.6, 1H), 7.20 (d, J = 7.2, 1H), 6.80 (d, J = 8.8,2H), 6.32 (s, 1H), 2.93 (s, 7H), 2.35 (s, 3H) 82 ¹H NMR (300 MHz, CDCl₃)δ 7.92 (d, J = 8.9, 1H), 7.82-7.70 (m, 2H), 7.66 (d, J = 7.8, 1H), 7.59(t, J = 7.6, 1H), 7.30 (dd, J = 6.0, 13.5, 1H), 7.14 (s, 1H), 7.11 (s,1H), 6.84 (d, J = 8.9, 1H), 2.32 (s, 3H) MS (ESI) [M + H]⁺ = 319 83 ¹HNMR (300 MHz, CDCl₃) δ 7.93-7.86 (m, 1H), 7.85 (s, 1H), 7.82 (d, J =8.4, 1H), 7.59 (dd, J = 8.2, 15.5, 2H), 7.44-7.38 (m, 1H), 7.29 (dd, J =8.3, 16.8, 2H), 6.91 (d, J = 9.0, 1H), 6.87 (d, J = 8.3, 1H) MS (ESI)[M + H]⁺ = 305 84 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 8.1, 1H), 7.92(d, J = 8.9, 1H), 7.85 (d, J = 8.4, 1H), 7.63 (d, J = 7.6, 1H), 7.58 (d,J = 7.3, 1H), 7.30 (dd, J = 6.8, 14.8, 3H), 7.02 (t, J = 7.8, 1H), 6.89(d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 305 86 ¹H NMR (300 MHz, CDCl₃) δ7.93 (d, J = 8.9, 1H), 7.83 (d, J = 8.3, 1H), 7.70 (d, J = 12.0, 1H),7.61 (dd, J = 7.9, 18.1, 2H), 7.32 (d, J = 7.9, 1H), 7.31-7.25 (m, 1H),7.21 (t, J = 6.5, 1H), 6.92 (d, J = 8.9, 1H), 6.79-6.68 (m, 1H) MS (ESI)[M + H]⁺ = 239 87 ¹H NMR (300 MHz, CDCl₃) δ 8.27 (s, 1H), 7.76 (d, J =8.9, 1H), 7.67 (d, J = 7.5, 1H), 7.51 (d, J = 8.2, 1H), 7.45 (d, J =7.9, 1H), 7.28 (d, J = 8.2, 1H), 7.14 (t, J = 7.8, 1H), 6.86 (d, J =10.1, 1H), 6.76 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 339 88 ¹H NMR (300MHz, CDCl₃) δ 8.11 (dt, J = 2.1, 12.1, 1H), 7.76 (d, J = 8.9, 1H), 7.66(dd, J = 1.2, 7.6, 1H), 7.45 (dd, J = 1.1, 8.0, 1H), 7.22 (dd, J = 1.4,7.2, 2H), 7.18 (d, J = 7.6, 1H), 7.12 (d, J = 7.8, 1H), 6.75 (d, J =8.9, 1H), 6.69 (d, J = 7.9, 1H) MS (ESI) [M + H]⁺ = 273 89 ¹H NMR (300MHz, DMSO) δ 11.38 (s, 1H), 8.41 (d, J = 9.1, 1H), 7.93 (d, J = 7.8,1H), 7.80 (dt, J = 8.1, 20.9, 4H), 7.50 (d, J = 7.8, 3H), 7.36 (d, J =9.3, 1H) 90 ¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J = 9.1, 2H), 7.79 (d, J= 8.9, 1H), 7.67 (dd, J = 1.2, 7.6, 1H), 7.48 (dd, J = 1.1, 8.0, 1H),7.18 (s, 3H), 6.89 (s, 1H), 6.75 (d, J = 8.9, 1H) ¹³C NMR (75 MHz,CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25, 131.13, 130.13, 126.55,125.42, 123.45, 122.50, 122.17, 120.49, 119.10, 113.24. MS (ESI) [M +H]⁺ = 339 91 ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 8.54 (s, 1H), 8.46(d, J = 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H),7.67 (d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9,1H) 92 ¹H NMR (300 MHz, CDCl₃) δ 8.67 (d, J = 7.9, 1H), 7.83 (d, J =8.3, 1H), 7.71 (s, 1H), 7.69-7.61 (m, 1H), 7.55 (dd, J = 7.5, 14.4, 2H),7.29 (d, J = 7.8, 1H), 6.80 (d, J = 7.4, 1H) 93 ¹H NMR (300 MHz, CDCl₃)δ 9.21 (dd, J = 1.5, 8.4, 1H), 7.85 (d, J = 8.4, 1H), 7.73 (s, 1H), 7.58(d, J = 7.8, 1H), 7.53 (dd, J = 1.3, 8.3, 1H), 7.40-7.35 (m, 1H), 7.32(dd, J = 1.1, 4.6, 1H), 7.31-7.24 (m, 2H), 7.04 (s, 1H), 7.02-6.94 (m,1H), 2.38 (s, 3H) 94 ¹H NMR (300 MHz, CDCl₃) δ 8.16 (d, J = 8.7, 1H),7.83 (d, J = 8.9, 1H), 7.63 (d, J = 7.6, 1H), 7.48 (d, J = 8.0, 1H),7.13 (t, J = 7.8, 1H), 7.08 (s, 1H), 7.04 (s, 2H), 6.81 (d, J = 8.9,2H), 2.27 (s, 3H) MS (ESI) [M + H]⁺ = 353 95 ¹H NMR (300 MHz, MeOD) δ8.42 (s, 1H), 7.94 (d, J = 7.9, 1H), 7.83 (d, J = 8.1, 1H), 7.78 (d, J =7.1, 1H), 7.72 (d, J = 8.7, 2H), 7.58 (d, J = 8.2, 3H), 2.60 (s, 3H) MS(ESI) [M + H]⁺ = 319 96 ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J = 8.9, 1H),7.70 (d, J = 8.9, 1H), 7.64 (d, J = 8.9, 2H), 7.59 (d, J = 2.1, 1H),7.50 (dd, J = 2.3, 8.9, 1H), 7.19 (d, J = 8.6, 2H), 6.85 (d, J = 8.9,1H) MS (ESI) [M + H]⁺ = 281 97 ¹H NMR (300 MHz, MeOD) δ 8.11 (d, J =8.4, 1H), 7.81 (s, 2H), 7.62 (d, J = 8.7, 3H), 7.51 (d, J = 8.3, 2H),7.12 (s, 1H), 2.77 (s, 3H) MS (ESI) [M + H]⁺ = 319 98 MS (ESI) [M + H]⁺= 383-385 99 MS (ESI) [M + H]⁺ = 320 100 MS (ESI) [M + H]⁺ = 316 101 ¹HNMR (300 MHz, CDCl₃) δ 7.82 (d, J = 8.9, 1H), 7.70-7.63 (m, 1H), 7.51(dd, J = 5.3, 7.6, 3H), 7.14 (t, J = 7.8, 1H), 6.91 (d, J = 8.8, 3H),6.85 (d, J = 9.0, 2H), 3.96 (t, J = 6.5, 2H), 1.84-1.68 (m, 3H), 1.49(dd, J = 7.4, 15.0, 3H), 0.97 (t, J = 7.4, 3H) MS (ESI) [M + H]⁺ = 327102 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J = 8.5,1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) MS (ESI) [M + H]⁺ = 313 103 MS (ESI) [M + H]⁺ =334 104 ¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J = 2.5, 1H), 7.89 (d, J =8.8, 1H), 7.72 (d, J = 7.6, 1H), 7.63 (dd, J = 2.5, 8.9, 1H), 7.53 (d, J= 8.0, 1H), 7.23 (dd, J = 6.2, 14.0, 2H), 7.04 (s, 1H), 6.81 (d, J =8.8, 1H) MS (ESI) [M + H]⁺ = 373 105 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (d,J = 2.6, 1H), 8.45 (d, J = 2.3, 1H), 8.01 (d, J = 8.1, 1H), 7.71 (d, J =7.8, 1H), 7.58 (s, 1H), 7.53 (d, J = 7.6, 1H), 7.51-7.45 (m, 2H),7.45-7.36 (m, 1H), 6.72-6.62 (m, 2H), 2.48 (s, 3H) 13C NMR (75 MHz,CDCl₃) δ 157.18, 154.80, 145.42, 143.80, 138.17, 135.04, 128.88, 128.76,127.17, 127.04, 120.69, 115.22, 106.73, 24.38 106 ¹H NMR (300 MHz, DMSO)δ 10.24 (s, 1H), 9.06 (d, J = 2.3, 1H), 8.65 (d, J = 1.8, 1H), 8.60 (d,J = 8.3, 1H), 8.56 (d, J = 4.5, 1H), 7.97 (dd, J = 8.2, 14.4, 2H), 7.69(t, J = 6.9, 1H), 7.59 (t, J = 7.4, 1H), 7.08 (dd, J = 4.6, 8.3, 1H) MS(ESI) [M + H]⁺ = 267 107 ¹H NMR (300 MHz, CDCl₃) δ 8.77 (dd, J = 1.5,4.3, 1H), 8.06 (dd, J = 10.8, 18.4, 3H), 7.93 (d, J = 2.4, 1H), 7.57(dd, J = 2.4, 9.0, 1H), 7.39 (ddd, J = 3.1, 8.3, 12.5, 3H), 6.93 (d, J =8.4, 1H), 6.89 (s, 1H), 2.29 (s, 3H) 108 ¹H NMR (300 MHz, CDCl₃) δ 8.72(dd, J = 1.6, 4.2, 1H), 8.61 (d, J = 2.4, 1H), 8.11 (d, J = 8.3, 1H),8.00 (d, J = 9.0, 1H), 7.91 (dd, J = 1.2, 5.0, 1H), 7.69 (dd, J = 2.4,9.1, 1H), 7.35-7.26 (m, 2H), 7.01 (dd, J = 1.2, 7.9, 1H), 6.77 (dd, J =5.1, 7.8, 1H), 3.93 (s, 3H) 109 ¹H NMR (300 MHz, CDCl₃) δ 9.68 (s, 1H),8.21 (s, 2H), 7.94 (d, J = 8.9, 1H), 7.79 (d, J = 9.2, 1H), 7.67 (d, J =2.3, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.34 (d, J = 8.9, 1H) MS (ESI)[M + H]⁺ = 257 110 1H NMR (300 MHz, CDCl₃) δ 10.32 (s, 1H), 8.33-8.21(m, 2H), 8.05 (d, J = 8.9, 1H), 8.00 (dd, J = 1.2, 7.6, 1H), 7.69 (dd, J= 1.1, 7.8, 1H), 7.61 (s, 1H), 7.30-7.22 (m, 3H), 7.16 (d, J = 8.8, 1H).MS (ESI) [M + H]⁺ = 301-303 111 ¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J =8.9, 1H), 7.70-7.63 (m, 1H), 7.51 (dd, J = 5.3, 7.6, 3H), 7.14 (t, J =7.8, 1H), 6.91 (d, J = 8.8, 3H), 6.85 (d, J = 9.0, 2H), 3.96 (t, J =6.5, 2H), 1.84-1.68 (m, 3H), 1.49 (dd, J = 7.4, 15.0, 3H), 0.97 (t, J =7.4, 3H) 112 ¹H NMR (300 MHz, CDCl₃) δ 7.89 (d, J = 8.9, 1H), 7.76 (d, J= 8.5, 1H), 7.63 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.8, 2H),7.38-7.24 (m, 3H), 7.09 (d, J = 7.4, 1H), 7.02 (dd, J = 2.4, 8.8, 4H),6.90 (d, J = 8.9, 1H) ¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48,142.18, 138.20, 137.55, 135.74, 129.71, 126.99, 125.35, 123.84, 114.75.MS (ESI) [M + H]⁺ = 255 113 ¹H NMR (300 MHz, CDCl₃) δ 9.74 (s, 1H), 8.20(s, 2H), 8.03 (d, J = 8.6, 1H), 7.87 (d, J = 7.6, 1H), 7.80 (s, 1H),7.70 (d, J = 8.0, 1H), 7.63 (t, J = 7.7, 1H), 7.37 (t, J = 7.4, 1H),7.30 (d, J = 8.7, 1H) 114 ¹H NMR (300 MHz, CDCl₃) δ 9.67 (s, 1H),8.34-8.12 (m, 2H), 7.84 (d, J = 8.0, 2H), 7.70-7.54 (m, 1H), 7.38 (t, J= 7.6, 1H), 7.17 (s, 1H), 2.61 (s, 3H) MS (ESI) [M + H]⁺ = 237 115 ¹HNMR (300 MHz, CDCl₃) δ 10.15 (s, 1H), 8.24-8.12 (m, 2H), 7.79 (s, 1H),7.71 (s, 1H), 7.55 (t, J = 8.3, 2H), 7.30 (t, J = 7.9, 1H), 2.38 (s, 3H)MS (ESI) [M + H]⁺ = 237 116 MS (ESI) [M + H]⁺ = 240 117 MS (ESI) [M +H]⁺ = 253 118 MS (ESI) [M + H]⁺ = 222 119 MS (ESI) [M + H]⁺ = 256 121 MS(ESI) [M + H]⁺ = 222 124 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.95(dd, J = 1.3, 8.2, 1H), 7.87-7.78 (m, 3H), 7.70-7.61 (m, 1H), 7.55-7.47(m, 1H), 7.26 (dd, J = 2.4, 6.5, 3H), 6.90 (s, 1H) MS (ESI) [M + H]⁺ =306 125 ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.03 (d, J = 9.5, 1H),7.92 (d, J = 8.2, 1H), 7.73 (d, J = 8.2, 1H), 7.61 (t, J = 7.3, 1H),7.46 (t, J = 7.2, 1H), 7.13 (s, 2H), 6.84 (s, 1H), 2.35 (s, 3H) 126 ¹HNMR (300 MHz, CDCl₃) δ 8.40 (s, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.2,1H), 7.84 (d, J = 8.2, 1H), 7.65 (t, J = 7.4, 1H), 7.53 (d, J = 7.1,1H), 7.48 (d, J = 7.2, 1H), 7.35 (t, J = 8.2, 1H), 7.22 (s, 1H), 6.94(d, J = 8.1, 1H) 127 ¹H NMR (300 MHz, CDCl₃) δ 8.85 (dd, J = 1.0, 8.3,1H), 8.47 (s, 1H), 7.96 (d, J = 8.2, 1H), 7.85 (d, J = 8.3, 1H),7.72-7.61 (m, 1H), 7.57-7.47 (m, 1H), 7.42-7.36 (m, 1H), 7.33 (d, J =10.0, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H) 128 ¹H NMR (300 MHz, CDCl₃) δ9.17 (s, 1H), 8.68 (d, J = 9.1, 1H), 8.64 (d, J = 4.8, 2H), 8.15 (d, J =9.1, 1H), 7.87 (d, J = 8.4, 1H), 7.76 (d, J = 8.1, 1H), 7.64 (t, J =7.7, 1H), 7.39 (t, J = 7.5, 1H), 6.87 (t, J = 4.8, 1H) ¹³C NMR (75 MHz,CDCl3) δ 158.34, 138.07, 129.85, 127.63, 127.31, 124.34, 114.20, 113.90.129 ¹H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.73 (d, J = 21.2, 3H), 8.17(s, 1H), 7.73 (d, J = 20.3, 2H), 7.28 (d, J = 9.6, 2H), 6.91 (s, 1H) 130¹H NMR (300 MHz, CDCl₃) δ 9.05 (s, 1H), 8.64 (d, J = 4.8, 2H), 8.52 (s,1H), 7.89 (dd, J = 8.5, 14.6, 2H), 7.63 (t, J = 7.5, 1H), 7.41 (t, J =7.4, 1H), 6.86 (t, J = 4.8, 1H), 2.74 (s, 3H) MS (ESI) [M + H]⁺ = 237132 ¹H NMR (300 MHz, CDCl₃) δ 8.86 (d, J = 2.6, 1H), 8.70 (d, J = 2.5,1H), 8.32 (d, J = 1.1, 1H), 8.25-8.21 (m, 1H), 8.10 (d, J = 2.7, 1H),8.06 (d, J = 8.3, 1H), 7.82 (dd, J = 1.2, 7.9, 1H), 7.66-7.51 (m, 3H),6.89 (s, 1H) 135 ¹H NMR (300 MHz, CDCl₃) δ 9.09 (s, 1H), 8.71 (s, 1H),8.54 (d, J = 8.4, 1H), 8.37 (dd, J = 1.0, 4.9, 1H), 7.96 (d, J = 8.2,1H), 7.85 (d, J = 8.3, 1H), 7.82-7.74 (m, 1H), 7.66 (t, J = 7.6, 1H),7.52 (dd, J = 7.0, 8.1, 1H), 7.02 (dd, J = 5.0, 7.2, 1H) MS (ESI) [M +H]⁺ = 223 136 ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30(s, 1H), 8.20 (d, J = 5.1, 1H), 7.94 (d, J = 8.1, 1H), 7.84 (d, J = 8.2,1H), 7.64 (t, J = 7.6, 1H), 7.49 (t, J = 8.1, 1H), 6.83 (d, J = 5.0,1H), 2.43 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55,147.40, 140.93, 139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70,113.75, 21.87. MS (ESI) [M + H]⁺ = 237 137 ¹H NMR (300 MHz, DMSO) δ11.10 (s, 1H), 9.03 (s, 1H), 8.82-8.75 (m, 1H), 8.56 (d, J = 8.9, 1H),8.24 (dd, J = 2.3, 8.9, 1H), 7.96 (dd, J = 1.2, 8.2, 1H), 7.87 (dd, J =1.0, 8.3, 1H), 7.79-7.71 (m, 1H), 7.61 (ddd, J = 1.4, 7.0, 8.3, 1H) MS(ESI) [M + H]⁺ = 248 138 ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 8.53(s, 1H), 8.20 (d, J = 8.3, 1H), 7.93 (d, J = 8.2, 1H), 7.81 (d, J = 8.3,1H), 7.62 (td, J = 3.4, 8.1, 2H), 7.53-7.43 (m, 1H), 6.83 (d, J = 7.4,1H), 2.48 (s, 3H) ¹³C NMR (75 MHz, CDCl₃) δ 156.86, 152.27, 148.40,140.92, 139.70, 139.00, 138.35, 130.42, 129.13, 127.14, 126.27, 117.76,110.01, 24.15. MS (ESI) [M + H]⁺ = 237 139 ¹H NMR (300 MHz, CDCl₃) δ8.53 (s, 1H), 8.20 (d, J = 4.8, 1H), 8.04 (d, J = 8.3, 1H), 7.92 (d, J =8.4, 1H), 7.87 (s, 1H), 7.79 (t, J = 7.6, 1H), 7.60 (t, J = 7.6, 1H),6.88 (d, J = 4.7, 1H), 2.46 (s, 3H) 140 ¹H NMR (300 MHz, CDCl₃) δ 9.93(s, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.1, 1H), 7.99 (s, 1H), 7.82 (d, J =8.2, 1H), 7.69 (t, J = 7.6, 1H), 7.59 (t, J = 8.2, 1H), 2.53 (s, 4H) 141¹H NMR (300 MHz, CDCl₃) δ 9.72 (s, 1H), 9.35 (s, 1H), 8.30 (d, J = 5.0,1H), 8.05 (d, J = 7.7, 1H), 7.87 (d, J = 7.0, 1H), 7.66 (dd, J = 7.4,16.9, 3H), 6.92 (d, J = 4.9, 1H), 2.58 (s, 3H) 143 ¹H NMR (300 MHz,DMSO) δ 8.85 (s, 1H), 8.42 (d, J = 5.3, 1H), 7.96 (d, J = 9.1, 1H), 7.44(s, 1H), 7.30 (s, 4H), 7.28-7.21 (m, 2H), 6.66 (d, J = 5.3, 1H), 2.99(s, 6H) ¹³C NMR (75 MHz, DMSO) δ 156.82, 150.25, 149.69, 143.79, 141.71,125.95, 122.33, 118.88, 117.37, 115.95, 109.39, 104.92, 43.57 MS (ESI)[M + H]+ = 348 144 MS (ESI) [M + H]⁺ = 390 145 MS (ESI) [M + H]⁺ = 252146 ¹H NMR (300 MHz, DMSO) δ 9.34 (s, 1H), 8.59 (d, J = 5.2, 1H), 8.53(s, 1H), 8.13 (d, J = 5.1, 1H), 7.98 (d, J = 9.0, 1H), 7.66 (d, J = 9.1,1H), 6.80 (d, J = 5.2, 1H), 6.76 (s, 1H), 6.69 (d, J = 4.9, 1H), 4.00(s, 3H), 2.26 (s, 3H) ¹³C NMR (75 MHz, DMSO) δ 161.31, 155.67, 151.63,150.25, 147.77, 147.01, 142.97, 121.56, 119.16, 116.61, 114.75, 112.60,111.41, 98.91, 55.78, 20.66. MS (ESI) [M + H]⁺ = 266 147 MS (ESI) [M +H]⁺ = 279 149 MS (ESI) [M + H]⁺ = 318 150 MS (ESI) [M + H]⁺ = 280 151 ¹HNMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 8.04 (d, J = 8.3, 1H), 7.82 (d, J =8.9, 1H), 7.74 (d, J = 8.9, 1H), 7.60 (t, J = 7.8, 2H), 7.50 (dd, J =2.3, 8.9, 1H), 7.36 (d, J = 8.9, 1H), 6.79 (d, J = 7.4, 1H), 2.75 (q, J= 7.6, 2H), 1.30 (t, J = 7.6, 3H). MS (ESI) [M + H]⁺ = 284 152 ¹H NMR(300 MHz, CDCl₃) δ 8.30 (d, J = 8.5, 1H), 8.08 (s, 1H), 7.90 (d, J =9.0, 1H), 7.77 (d, J = 8.9, 1H), 7.65 (d, J = 2.2, 1H), 7.55 (td, J =2.0, 8.8, 2H), 7.39 (d, J = 9.0, 1H), 2.31 (s, 3H). MS (ESI) [M + H]⁺ =270 153 ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.54 (s, 1H), 8.46 (d, J= 8.8, 1H), 7.91 (dd, J = 5.5, 14.5, 2H), 7.79 (d, J = 8.9, 1H), 7.67(d, J = 2.1, 1H), 7.56 (dd, J = 2.3, 8.9, 1H), 7.35 (d, J = 8.9, 1H). MS(ESI) [M + H]⁺ = 324 154 ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.12 (d,J = 8.4, 1H), 7.73 (d, J = 8.2, 2H), 7.66 (d, J = 10.0, 1H), 7.53 (s,1H), 7.25 (s, 1H), 6.82 (s, 1H), 5.10 (s, 2H), 2.16 (s, 4H). MS (ESI)[M + H]⁺ = 285 155 ¹H NMR (300 MHz, CDCl₃) δ 7.68 (d, J = 8.3, 1H), 7.61(s, 1H), 7.56 (d, J = 11.5, 2H), 7.44 (d, J = 8.3, 1H), 7.38 (d, J =7.8, 1H), 7.13 (t, J = 7.4, 1H), 6.80 (d, J = 8.7, 2H), 3.85 (t, J =6.5, 2H), 2.18 (s, 3H), 1.73-1.58 (m, 2H), 1.48-1.31 (m, 2H), 0.88 (t, J= 7.3, 3H) MS (ESI) [M + H]⁺ = 307 156 ¹H NMR (300 MHz, CDCl₃) δ 7.75(d, J = 9.1, 1H), 7.62 (d, J = 8.9, 1H), 7.58 (d, J = 2.2, 1H), 7.48(dd, J = 2.4, 8.9, 1H), 7.30 (d, J = 8.9, 2H), 6.86 (d, J = 9.0, 1H),6.77 (d, J = 8.9, 2H), 6.71 (s, 1H), 2.97 (s, 6H) MS (ESI) [M + H]⁺ =298 157 ¹H NMR (300 MHz, CDCl₃) δ 7.98 (d, J = 2.6, 1H), 7.89 (d, J =8.9, 1H), 7.72 (d, J = 7.5, 1H), 7.62 (dd, J = 2.6, 8.8, 1H), 7.55 (d, J= 7.8, 1H), 7.20 (t, J = 7.8, 1H), 6.95 (d, J = 8.9, 1H), 6.84 (d, J =8.9, 1H), 6.79 (s, 1H), 3.91 (s, 3H) MS (ESI) [M + H]⁺ = 319 158 ¹H NMR(300 MHz, CDCl₃) δ 7.89 (d, J = 9.0, 1H), 7.70 (dd, J = 1.2, 7.5, 1H),7.56 (dd, J = 1.1, 8.0, 1H), 7.30 (d, J = 8.6, 1H), 7.20 (t, J = 7.8,1H), 6.71 (t, J = 5.9, 2H), 6.64 (d, J = 9.5, 1H). MS (ESI) [M + H]⁺ =354 159 ¹H NMR (300 MHz, CDCl₃) δ 8.80 (d, J = 2.6, 1H), 8.37 (d, J =2.6, 1H), 8.01 (d, J = 8.1, 1H), 7.91 (dd, J = 1.6, 4.9, 1H), 7.78-7.70(m, 1H), 7.58-7.43 (m, 2H), 7.09 (dd, J = 1.6, 7.6, 1H), 6.84 (dd, J =4.9, 7.6, 1H), 6.69 (s, 1H), 3.82-3.07 (m, 2H). 160 ¹H NMR (300 MHz,CDCl₃) δ 9.68-8.90 (m, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.14 (d, J =5.0, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.8, 1H), 7.61 (d, J = 8.5, 1H),6.88 (d, J = 4.8, 1H), 2.46 (s, 3H) 161 ¹H NMR (300 MHz, CDCl₃) δ 9.98(s, 1H), 8.70 (s, 1H), 8.45 (s, 1H), 8.27 (d, J = 5.2, 1H), 7.94 (d, J =8.1, 1H), 7.84 (d, J = 8.2, 1H), 7.63 (t, J = 7.5, 1H), 7.48 (t, J =7.5, 1H), 6.87 (d, J = 5.0, 1H), 2.74 (q, J = 7.6, 2H), 1.34 (t, J =7.6, 3H). MS (ESI) [M + H]⁺ = 251 162 ¹H NMR (300 MHz, CDCl₃) δ 8.73 (s,1H), 8.70-8.60 (m, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.1,1H), 7.86 (d, J = 7.9, 1H), 7.68 (t, J = 8.2, 1H), 7.54 (t, J = 8.1,1H), 2.49 (s, 3H) MS (ESI) [M + H]⁺ = 315 163 ¹H NMR (300 MHz, CDCl₃) δ8.75 (s, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 8.2, 1H), 7.84(d, J = 8.3, 1H), 7.64 (t, J = 8.2, 1H), 7.49 (t, J = 7.0, 1H), 6.69 (s,1H), 2.45 (s, 3H), 2.38 (s, 3H) MS (ESI) [M + H]⁺ = 251 164 ¹H NMR (300MHz, DMSO) δ 10.46 (s, 1H), 9.00 (s, 1H), 8.41 (s, 1H), 8.24 (d, J =3.0, 1H), 7.90 (d, J = 8.2, 1H), 7.79 (d, J = 8.3, 1H), 7.69 (t, J =7.0, 1H), 7.52 (t, J = 7.4, 1H), 6.98 (d, J = 4.8, 1H), 5.45 (q, J =5.6, 1H), 4.58 (d, J = 5.7, 2H). MS (ESI) [M + H]⁺ = 253 165 ¹H NMR (300MHz, CDCl₃) δ 9.07 (s, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.18 (s, 1H),8.09-8.01 (m, 1H), 7.94 (d, J = 8.4, 1H), 7.81-7.71 (m, 1H), 7.69-7.59(m, 1H), 2.80 (s, 3H) MS (ESI) [M + H]⁺ = 282 166 ¹H NMR (300 MHz,CDCl₃) δ 8.49 (d, J = 5.0, 1H), 7.77 (d, J = 9.0, 1H), 7.32 (d, J = 2.0,1H), 7.12 (d, J = 9.0, 2H), 6.99 (dd, J = 2.0, J = 9.0, 1H), 6.82 (d, J= 9.0, 2H), 6.57 (d, J = 5.0, 1H), 5.78 (s, 1H), 3.74 (s, 3H), 3.17 (s,4H), 2.62 (s, 4H), 2.34 (s, 3H) 167 MS (ESI) [M + H]⁺ = 335 168 MS (ESI)[M + H]⁺ = 321

The following examples illustrate in detail the preparation of compounds(51), (64), (110), (143) and (148) as described above. The structures ofthe products obtained have been confirmed at least by NMR spectra.

Embodiment I: Examples

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a 1.1 molar ratio with respect to the compound of formula(III) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃, in a2.8 molar ratio, in the presence of a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in a 2 mol %amount relative to the total amount of compound of formula (III), and inthe presence of a catalyst, such as Pd(OAc)₂ or Pd₂dba₃ in a 2 mol %amount relative to the total amount of compound of formula (III). Thereaction mixture is then heated at 90° C., and stirred during 20 hours,under argon. The reaction mixture is concentrated under reduced pressureand the resulting residue is diluted with ethyl acetate. The organicphase is then washed twice with water, dried on magnesium sulphate,filtered and concentrated under reduced pressure. The residue could thenbe purified by column chromatography on silica gel to yield purecompounds (51), (64), (110), and (143).

According to route (B), the compound of formula (V) is placed in aprotic solvent such as tert-butanol. The compound of formula (VI) isthen added in a 1.1 molar ratio with respect to the compound of formula(V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %amount relative to the total amount of compound of formula (V), and inthe presence of a Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (V). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compound (148).

Example 1: Compound (51) of Table I

According to route (A), a mixture of 2,8-dichloroquinoline (98.5 mg) and2-amino-4,6-dimethylpyridine (67.1 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (51) (99.7 mg).

Example 2: Compound (64) of Table I

According to route (A), a mixture of 2-chloro-5-nitroquinoline (100.0mg) and 2-amino-4-methylpyridine (57.6 mg), Pd₂dba₃ (20 mg), XantPhos(30 mg) and K₂CO₃ (270 mg) in 3 mL of t-BuOH gave compound (64) (14.0mg).

The preparation of 2-chloro-5-nitroquinoline is described in Patentapplication WO2009/23844.

Example 3: Compound (110) of Table I

According to route (A), a mixture of 8-bromo-2-chloroquinoline (500 mg)and aminopyrazine (216 mg), Pd₂dba₃ (95 mg), XantPhos (120 mg) and K₂CO₃(1.15 g) in 12 mL of t-BuOH gave compound (110) (245 mg).

The preparation of 8-bromo-2-chloroquinoline is described in Cottet, F.et al. Eur. J. Org. Chem. 2003, 8, 1559.

Example 4: Compound (143) of Table I

According to route (A), a mixture of7-chloro-4-(N,N-dimethylamino)quinoline (500 mg),4-trifluoromethoxyaniline (0.257 mL), Pd₂dba₃ (110 mg), XPhos (115 mg)and K₂CO₃ (1 g) in 10 mL of t-BuOH gave compound (143) (410 mg).

The preparation of 7-chloro-4-(N,N-dimethylamino)quinoline is describedin Sanchez-Martin, R. et al. J. Med. Chem. 2005, 48, 3354.

Example 5: Compound (148) of Table I

According to route (B), a mixture of 5,8-dimethylisoquinolin-6-amine (59mg) and 2-bromo-5-methylpyridine (86 mg), Pd(OAc)₂ (2.2 mg), XantPhos(5.8 mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (148) (48mg).

The preparation of 5,8-dimethylisoquinolin-6-amine is described inAustralian Journal of Chemistry 1969, 22, 2489.

1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.52 (d, J=6.0, 1H), 8.07 (s,1H), 7.72 (d, J=6.0, 1H), 7.51 (s, 1H), 7.36 (dd, J=2.1, 8.4, 1H), 6.69(d, J=8.3, 2H), 2.72 (s, 3H), 2.48 (s, 3H), 2.26 (s, 3H)

MS (ESI) [M+H]+=264

Example 6: Pharmacological Data

Standard Operating Procedure:

Effect of drug compounds on invasion of MDA-MB231-D3H2LN cells intocollagen

Background:

A key step in the generation of tumor metastasis is tumor cell invasionof the extracellular matrix, a major component of which is collagen.Therefore, the invasion of tumor cells into collagen in vitro may beindicative of tumor metastasis in vivo. E. g., MDA-MB231-luc-D3H2LNmouse breast cancer cells display both higher invasion into collagen invitro and a higher metastatic potential in vivo as compared to MDA-MB231cells (from which they were derived). Using these MDA-MB231-luc-D3H2LNcells as a model, the aim of the experiment described here is toidentify drug compounds that inhibit the invasion of tumor cells intocollagen in vitro, therefore potentially inhibiting also the generationof tumor metastasis in vivo.

Assay Principle:

Step 1:

Preparation of cells at the bottom of a collagen gel: Cells weresuspended in a liquid collagen solution (4° C.), distributed intoBSA-coated wells, and then collected at the bottom of the wells bycentrifugation. The collagen was then solidified by incubation at 37° C.The BSA coating improves the adhesion of the collagen gel.

Step 2:

Pre-treatment with the compounds to be tested: Concentrated drugsolutions were then added on top of the collagen, and cells arepre-incubated for 24 h with the drugs at low serum conditions (0.025%FBS).

Step 3:

Stimulation of invasion: Medium with 5% FBS was then added in order tostimulate invasion of the cells into the collagen gel.

Step 4:

Fixation and staining: Following another 24 h incubation, cells werefixed and nuclei were stained.

Step 5:

Analysis: Finally, plates were analyzed using an automated microscope.Fluorescent beads that have been included into the BSA coating serve todetect the bottom of the wells. Pictures of the stained nuclei weretaken at the same level (0 μm) as well as 25 μm and 50 μm above.

Note:

In order to detect possible toxic effects, all compounds were tested inparallel in a viability assay. The viability assay was performed inparallel on serum-starved cells (as in the invasion assay) vs. cellsunder normal culture conditions (10% FBS).

Materials:

General Equipment:

Freezer (−20° C.), refrigerator (4° C.), ice machine, water bath (37°C.), incubator (37° C./5% CO₂), cell culture hood, vortex, vacuum pump,microscope, Malassez cell, Pipet aid, micropipettes (for pipetting1-1000 μl), multichannel pipettes (for pipetting 20-200 μl), standardcell culture centrifuge, refrigerated centrifuge for 96 well plates.

General Consumables:

Sterile 96 well cell culture plates (for the viability assay), steriletubes (1.5/15/50 ml), sterile pipettes (5/10/25 ml), sterilemicropipette tips (for pipetting 1-1000 μl), sterile Pasteur pipettes,sterile reagent reservoirs.

General Products:

Sterile PBS, sterile Milli-Q water, DMSO, decomplemented FBS (frozenaliquots), 0.1 N NaOH, 1 M Hepes, MEM without serum (not older than 1month), 2.5×MEM without serum (not older than 1 month), MEM with 10% FBS(not older than one month), 0.25% trypsin/1 mM EDTA solution, 37%formaldehyde solution.

Specific Equipment:

plate reader: Tecan Infinite F200

automated microscope: Cellomics ArrayScan VTI HCS Reader

Specific Consumables:

sterile black 96 well plates (for the invasion assay): Perkin ElmerViewPlate-96 F TC, ref 6005225

sterile 96 deep well polypropylene plates (for drug preparation):Starlab, ref. S1896-5110

Specific Products:

rat tail collagen, type 1: BD Biosciences, ref 354236 (note: each newlot has to be validated)

red fluorescent beads (1 μm diameter): Invitrogen, ref. F13083

Y-27632 (5 mM aqueous solution): Calbiochem, ref. 688001 (in solution)or 688000 (dry powder)

BSA without fatty acids (sterile-filtered 4% aqueous solution): Sigma,ref. A8806 (dry powder)

Hoechst 33342 nuclear stain (10 mg/ml): Invitrogen, ref. H3570

MTS reagent: Promega CellTiter CellTiter 96® AQueous One SolutionReagent, ref. G3581

drug compounds to be tested: generally 25 or 50 mM in 100% DMSO(aliquots stored at −20° C., then at 4° C. for max. 3 months)

MDA-MB231-luc-D3H2LN cells:

Limits for the cell cultures to be used in the assays:

total passage number: max. 30

last passage: between 2 and 4 days before, between 1:3 and 1:20

cell density: between 50 and 90% (optimally 70%) (between 1 and 2×106cells per 100 mm dish)

Experimental Procedures:

General Considerations: Controls and Plate Maps:

Invasion assay: Negative control: No drug (just DMSO at equivalentconcentration). Positive control: 10 μM Y-27632. To avoid edge effects,only the 60 central wells B2-G11 were used; lines A and H as well ascolumns 1 and 12 remain free. Each drug was tested at least intriplicate. The positive and negative controls were tested in doubletriplicates at different positions on each plate. Typical plate map(−=negative control, +=positive control, 1-16=16 different drugcompounds):

1 2 3 4 5 6 7 8 9 10 11 12 A B − 1 2 3 4 5 6 7 8 + C − 1 2 3 4 5 6 7 8 +D − 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 − F + 9 10 11 12 13 1415 16 − G + 9 10 11 12 13 14 15 16 − H

Viability Assays:

No additional controls. The MTS viability assay was based oncolorimetric detection of a product generated by the mitochondrialactivity of the cells. Each drug was tested at least in duplicate. Todetect potential direct interactions with the assay substrate, each drugwas also tested in absence of cells (background signals). Typical platemap (controls and drug compounds as in the invasion assay, lines A-B andE-F: with cells, lines C-D and G-H: without cells; each 1 plate with 10%vs. 0.025% FBS):

1 2 3 4 5 6 7 8 9 10 11 12 A − 1 2 3 4 5 6 7 8 + B − 1 2 3 4 5 6 7 8 + C− 1 2 3 4 5 6 7 8 + D − 1 2 3 4 5 6 7 8 + E + 9 10 11 12 13 14 15 16 −F + 9 10 11 12 13 14 15 16 − G + 9 10 11 12 13 14 15 16 − H + 9 10 11 1213 14 15 16 −

The volumes or other quantities indicated in the following are requiredfor testing 16 drug compounds per 96 wells-plate at 5 μM each (+controls) in an invasion assay and each one viability assay onserum-starved cells vs. cells under normal culture conditions accordingto the plate maps above. According to the number of tested compounds,the volumes and other quantities should be adapted for testing more orless compounds or different concentrations.

Day 1: Preparation and Treatment of the Cells (all Steps are PerformedUnder a Cell Culture Hood):

Preparation of 100× concentrated drug solutions in 10% DMSO:

prepare 10% DMSO in sterile PBS: 1.8 ml sterile PBS+0.2 ml DMSO

prepare 100 μl/well 10% DMSO in PBS in 16 wells of a sterile 96 wellpolypropylene plate

add each 1 or 2 μl of the 50 or 25 mM compound stock solutions,respectively

mix by pipetting up and down

Preparation of 4× concentrated drug and control solutions in 0.4% DMSOin MEM+0.1% FBS:

Prepare MEM+0.1% FBS: 12 ml MEM without serum+12 μl FBS (freshly thawedaliquot)

prepare 480 μl/well MEM+0.1% FBS in 20 wells of a sterile 96 deep wellpolypropylene plate

negative controls (no drug): add each 20 μl 10% DMSO in sterile PBS

positive controls (Y-27632): add each 14 μl sterile PBS+2 μl DMSO+4 μl 5mM Y-27632 (freshly thawed aliquot)

drug compounds: add each 20 μl of the 100× concentrated drug solutionsin 10% DMSO

mix by pipetting up and down

store at RT until use

Coating of the Plates for the Invasion Assay:

mix 9.5 ml MEM without serum+0.5 ml 4% BSA without fatty acids+1 μlvortexed fluorescent beads (i. e. dilute 1:10000), vortex, distribute100 μl/well into the plate for the invasion assay

centrifuge 30′ with 1800×g at 4° C. (e. g. 3000 rpm in a Jouan GR412centrifuge)

remove supernatants by aspiration

Preparation of a 10×106 Cells/ml Cell Suspension (During theCentrifugation of the Plates):

-   -   remove medium, wash cells with ˜10 ml/dish PBS, add 1 ml/dish        0.25% trypsin/1 mM EDTA

incubate 30-60 s at 37° C.

add 5-10 ml/dish pre-warmed MEM+10% FBS

homogenize by pipetting up and down using a 10 ml pipette, pool all

count cells using a Malassez cell

centrifuge 2×106 (or more) cells for 5′ with 150×g at RT (850 rpm in astd. cell culture centrifuge)

remove supernatant, resuspend cell pellet in 0.2 ml (or more,respectively) MEM without serum, yielding 10×106 cells/ml

Preparation of the Invasion Assay (on Ice; Start During theCentrifugation of the Cells):

mix on ice in a pre-chilled tube: example for a 3.4 mg/ml collagen stocksolution; volumes of collagen and water to be adapted according to thestock concentration of each collagen lot:

2.8 ml 2.5×MEM

441 μl water

140 μl 1 M Hepes

49 μl 1 N NaOH

3.5 ml 3.4 mg/ml collagen stock solution (yielding 1.7 mg/ml collagen in7 ml)

homogenize by pipetting gently up and down (keep on ice)

add 70 μl of the 10×106 cells/ml cell suspension, homogenize bypipetting gently up and down (yields 0.1×106 cells/ml in 1.7 mg/mlcollagen in 7 ml 1×MEM+20 μM Hepes) (keep on ice)

distribute 100 μl/well (i. e. 10000 cells/well) into the coated wells ofthe plate for the invasion assay (all on ice)

centrifuge 5′ with 200×g at 4° C. (e. g. 1000 rpm in a Jouan GR412centrifuge)

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂ (solidification of the collagen)

Preparation of the Viability Assay on Serum-Starved Cells:

add 50 μl of the 10×106 cells/ml cell suspension to 5 ml MEM withoutserum (yields 0.1×106 cells/nil)

distribute 100 μl/well of this suspension (i. e. 10000 cells/well) orMEM without serum without cells, respectively, into a standard 96 welltissue culture plate, according to the plate map above

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂

Preparation of the Viability Assay on Cells Under Normal CultureConditions:

add 30 μl of the 10×106 cells/ml cell suspension to 5 ml MEM+10% FBS(yields 0.06×106 cells/nil)

distribute 100 μl/well of this suspension (i. e. 6000 cells/well) orMEM+10% FBS without cells, respectively, into a standard 96 well tissueculture plate, according to the plate map above

add 200 μl/well PBS to all free wells

incubate 30′ at 37° C./5% CO₂

Treatment with the Drugs:

add each 33 μl/well of the 4× concentrated drug solutions in MEM+0.1%FBS to the corresponding wells in all three plates, according to theplate maps above

incubate 24 h at 37° C./5% CO₂

Day 2: Addition of FBS to Stimulate the Invasion:

Microscopic Observation after 24 h of Treatment:

examine the cells of the viability assays

Addition of FBS (Under a Cell Culture Hood):

prepare MEM+5% FBS: 7.2 ml MEM without serum+0.8 ml FBS (freshly thawedaliquot or rest of the aliquot thawed the day before if kept at 4° C.)

add 33 μl/well to all wells of invasion and viability assays

incubate 24 h at 37° C./5% CO₂

Day 3: Stop:

Microscopic Observation after 48 h of Treatment:

examine the cells of the viability assays

Viability Assays: MTS Assay:

add each 33 μl/well of the MTS reagent, incubate 2.5 h at 37° C./5% CO₂

shake and read absorbance at 490 nm (proportional to the viability)

calculate the background-corrected signals by subtracting the means ofthe background signals in absence of cells from the correspondingsignals in presence of cells

normalize the background-corrected signals with respect to the meansignal of the negative controls (no drug) (viabilities are thusexpressed in “% of control”)

Invasion Assays: Fixation and Staining (Formaldehyde Must be ManipulatedUnder a Fume Cupboard):

freshly prepare 1 μg/ml Hoechst 33342 in 18.5% formaldehyde: 5 ml PBS(not necessarily sterile)+5 ml 37% formaldehyde+1 μl 10 mg/ml Hoechst33342 (note: for one plate, a smaller volume would be sufficient, butthe minimal pipetted volume should not be below 1 μl)

add 50 μl/well to all wells of the invasion assay (yields 4.3%formaldehyde final)

seal with black film (provided with the plates)

incubate at least 7 h at RT

Day 3: 17 (Min. 7 h/Max. 2 Weeks after Fixation and Staining): Analysisof the Invasion Assay:

Lecture using the Cellomics ArrayScan VTI HCS Reader:

BioApplication: SpotDetector.V3

Plate type: Perkin Elmer 96 well

Parameters of the Assay Protocol:

objective: 10×(NA 0.45)

apotome: yes (resulting optical slice: 11.7 μM)

fields per well: 8

autofocus in each field

autofocus channel: 1

channel 1 (autofocus on, and photo of the fluorescent beads at thebottom of the wells): filter: XF93—TRITC; exposure time: usually between0.002 and 0.01 s

channel 2 (photo of the stained cells at the same level as thefluorescent beads): filter: XF100—Hoechst; exposure time: usuallybetween 0.02 and 0.1 s; z offset: 0 μM

channel 3 (photo of the stained cells 25 μM above the fluorescentbeads): filter: XF100—Hoechst; exposure time: usually between 0.02 and0.1 s; z offset: −25 μM

channel 4 (photo of the fluorescent cells 50 μM above the fluorescentbeads): filter: XF100—Hoechst; exposure time: usually between 0.02 and0.1 s; z offset: −50 μM

object identification: method: fixed threshold: 100-32767

object selection parameters: min. max. SpotArea: 20 1000000000000SpotShapeBFR: 0.2 1000 SpotShapeBAR: 0 1000 SpotAvgInten: 200 32767SpotTotalInten: ≤4000 (thus not limiting) 1000000000000 TargetAvgInten:0 32767 TargetTotalInten: 0 1000000000000

Analysis of the Results of the Scan Using vHCS Viewer:

export the results: for each well:

number of valid fields

number of objects in each valid field in each of the channels 2, 3 and 4(“field details”)

mean numbers of objects per valid field for each well, in each of thechannels 2, 3 and 4

exclude wells with less than 6 valid fields per well from furtheranalysis

visually check all photos for any apparent problems, such as badfocusing or obviously inhomogeneous collagen structure (“bubbles”, . . .), . . . ; in case of apparent problems: document, then exclude thecorresponding wells from further analysis

Further Analysis of the Results of the Invasion Assay (Using e. g.Excel):

For each well, the mean invasion distance was calculated as follows: (25μm×number of cells at 25 μm+50 μm×number cells at 50 μm)/sum of cells at0, 25 and 50 μm

For all four parameters (number of cells at 0 μm, number of cells at 25μm, number of cells at 50 μm, mean invasion distance of the countedcells), calculate means, SD and CV of the replicates (n=6 for thecontrols; n=3 for the samples).

Replicates having a CV≥50% (compound to be re-tested, or assay to berepeated if CV≥50% for the untreated negative control or the compoundY-27632-treated positive control) were invalidated. Y27632 is aselective inhibitor of the Rho-associated protein kinase p160ROCK of thefollowing formula:

The assay was validated only if the mean invasion distance of the cellstreated with 10 μM Y-27632 (positive control) was decreased by ≥40% ascompared to the untreated negative control.

Graphs were plotted of all four parameters (number of cells at 0 μm,number of cells at 25 μm, number of cells at 50 μm, mean invasiondistance of the counted cells).

Results

Anti-invasive effect at 5 μM on MDA-MB231 breast cancer cells (foldeffect compared to 10 μM Y-27632 ref compound)

Compound Invasion of MDA MB231 cells at 5 mM (family) (fold effect ofpositive control) 148 (Iee) 0.54 109 (Ie) 0.41 110 (Ie) 0.64 112 (Ie)0.26 143 (Iq) 0.8 144 (Iq) 0.73  63 (Ia) 0.69  64 (Ia) 1.16  6 (Ia) 0.63 18 (Ia) 0.52  45 (Ia) 0.50  30 (Ia) 0.33  35 (Ia) 0.26  36 (Ia) 0.43 37 (Ia) 0.34  48 (Ia) 0.63  53 (Ia) 0.27  51 (Ia) 1.06  52 (Ia) 0.27 58 (Ia) 0.33  61 (Ia) 0.34  58 (Ia) 0.33  55 (Ia) 0.27  56 (Ia) 0.26

The compounds according to the present invention demonstrated ananti-invasive effect predictive for their activity against cancer.

Therefore, the results of the tests carried out with the compoundsdescribed herein demonstrated properties that may be useful to inhibit,prevent and/or treat cancer. For example, the following types of cancersmay more be treated by the compounds according to the present invention:colorectal cancer, pancreatic cancer, lung cancer including non-smallcell lung cancer, breast cancer, bladder cancer, gall bladder cancer,thyroid cancer, melanoma, liver cancer, uterine/cervical cancer,oesophageal cancer, kidney cancer, ovarian cancer, prostate cancer, headand neck cancer, and stomach cancer, etc.

For this purpose an effective amount of a said compound may beadministered to a patient suffering from cancer.

The present disclosure is also related to the use of at least a compoundchosen among a compound of anyone of formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip),(Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168) asdefined above, or one of its pharmaceutically acceptable salts accordingto the present invention for the manufacture of a pharmaceuticalcomposition intended for the treatment of cancer.

The present disclosure also encompasses pharmaceutical compositionscomprising at least a compound chosen among new compounds of formula(Iq) or (Iee) as defined above and compounds (143), (144), (149), (166)and (167) as defined above or any pharmaceutically acceptable saltthereof.

Thus, these pharmaceutical compositions contain an effective amount ofsaid compound, and one or more pharmaceutical excipients.

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

In this context, the compounds described herein can be present in anypharmaceutical form suitable for enteral or parenteral administration,in association with appropriate excipients, for example in the form ofplain or coated tablets, hard gelatine, soft shell capsules and othercapsules, suppositories, or drinkable, such as suspensions, syrups, orinjectable solutions or suspensions, in doses which enable the dailyadministration of from 0.1 to 1000 mg of active substance.

The present disclosure is also related to the use of a compound ofanyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Iee) as definedabove, and compounds (1) to (168) as defined above, or one of itspharmaceutically acceptable salts according to the present invention forthe manufacture of a pharmaceutical composition intended for inhibiting,preventing and/or treating cancer.

The present disclosure further relates to a method of treatment ofpatients suffering from cancer, which comprises at least a step ofadministration to a patient suffering thereof of an effective amount ofa compound of anyone of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or(Iee) as defined above and (1) to (168) or one of its pharmaceuticallyacceptable salts.

Embodiment II (Aids)

In order to minimize the risk that these indole derivatives intercalatebetween DNA bases, the inventors developed novel compounds that areparticularly effective in treating diseases related to the splicingprocess, but which, in a surprising manner, have a cellular toxicitythat is clearly less than the indole derivatives of the prior art. Inaddition, these compounds are able to selectively inhibit certainsplicing events.

According to a first aspect, a subject-matter of the present inventionrelates to a compound of formula (I)

wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group and a (C₁-C₃)alkylgroup, said alkyl being optionally mono-substituted by a hydroxyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group,a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

T is N or C,

U is N or C,

and wherein at most four of the groups V, T, U, Z, Y, X and W are N,

and at least one of the groups T, U, Y, X and W is N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, Tis C, U is C and W is C, for use as an agent for preventing, inhibitingor treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is C,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is C and W is N, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is C, X is N, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and in ortho of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and is in ortho of the bond linked to NR″, Y is N, X is N, T is C,U is C and W is C, for use as an agent for preventing, inhibiting ortreating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is N and W is C, for use as an agent for preventing,inhibiting or treating AIDS.

The compounds of the invention may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of compounds offormula (I) include hydrobromide, tartrate, citrate, trifluoroacetate,ascorbate, hydrochloride, tartrate, triflate, maleate, mesylate,formate, acetate and fumarate.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

In the context of EMBODIMENT II of the present disclosure, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃        normal, secondary or tertiary saturated hydrocarbon. Examples        are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,    -   “(C₁-C₃)alkoxy” as used herein respectively refers to        O—(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.        Examples are, but are not limited to, methoxy, ethoxy,        1-propoxy, 2-propoxy,    -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively        to alkyl group and alkoxy group as above-defined, said groups        being substituted by at least one fluorine atom. Examples are        perfluoroalkyl groups, such as trifluoromethyl or        perfluoropropyl, and    -   “patient” may extend to humans or mammals, such as cats or dogs.

According to one preferred aspect, the present invention relates to acompound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in para of Z, Y is N, X is C, T is C, U is C and W is C, for use asan agent for preventing, inhibiting or treating AIDS.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating AIDS.

Another object of the present invention relates to a compound of thefollowing formula (I′):

wherein:

X1, X2 and X3 independently represent a nitrogen atom, or a CR8 group,at least one of X1 and X2 being a nitrogen atom;

R8 represents a hydrogen atom or a halogen atom, a hydroxyl, alkyl,trifluoroalkyl, ester, ether, such as a methoxy or trifluoromethoxygroup, or benzyl, optionally substituted, a nitro or a cyano group,preferably R8 represents a hydrogen atom,

when a ring A, defined below, is in position a, X4 represents a nitrogenatom or a CR8 group, and when a ring A is in position b, X4 represents acarbon atom part of the ring A,

R1, R2, R3 and R5 independently represent a hydrogen or a halogen atom,an alkyl, a trifluoroalkyl group, ether, such as a methoxy ortrifluoromethoxy group, or benzyl, optionally substituted, a nitro or acyano group.

when the ring A is at position b, R4 represents a hydrogen atom, ahalogen atom or an alkyl, a trifluoroalkyl, ester, ether group, such asa methoxy or trifluoromethoxy group, or benzyl, optionally substituted,and when the ring A is at position a, R4 is a carbon atom part of thering A,

R10 represents a carbon atom part of ring A,

R6 represents a hydrogen atom or an alkyl group,

A represents a ring at position a orb of formula I, said ring Acorresponding to:

wherein:

R7 represents a hydrogen, or halogen atom or an alkyl, hydroxyl or aminegroup which can be linear or branched and/or unsaturated and optionallysubstituted,

pharmaceutically acceptable salts of said compounds, isomers thereofand/or mixtures of the same,

with the exception of the following compound:

“Halogen atom” means the group comprising F, Cl, Br and I, preferablysaid halogen atom is a chlorine atom.

“Unsaturated” means that the group comprises at least one double bond.

All the compounds disclosed in the examples are in the scope of thepresent invention.

Preferably, X1 represents a CR8 group when X2 represents a nitrogengroup, and

X2 represents a CR8 group when X1 represents a nitrogen group.

Preferably, at least one of X3 and X4 is a nitrogen atom when the cycleA is in position a.

Preferably X3 and X4 are different, and even more preferably X3represents a CR8 group when X2 represents a nitrogen group or a and X4represents a CR8 group when X1 represents a nitrogen group.

Preferably, R1 represents a hydrogen atom or a methoxy group.

Preferably, R2, R3, R4 and R5 independently represent a hydrogen atom ora halogen atom or an alkyl, or benzyl, optionally substituted.

Preferably, R4 represents a hydrogen atom.

Preferably, R2 represents a hydrogen atom or a C1 to C4 alkyl group,preferably a methyl.

Preferably, R3, R5 and R6 independently represent a hydrogen atom.

Preferably, R7 represents a hydrogen, or halogen atom, more preferably ahydrogen or a chlorine atom.

Preferably, the ring A is attached at position a or b of the compound offormula I via the carbons numbered 1 and 2 in ring A.

Preferably, when the ring A is at position a, R4 is the carbon atomnumbered 2 of the ring A, more preferably R4 is the carbon atom numbered2 of the ring A and R10 is the carbon numbered 1.

Preferably, when a ring A is in position b, X4 is the carbon atomnumbered 1 of the ring A, more preferably, X4 is the carbon atomnumbered 1 of the ring A and R10 is the carbon numbered 2.

Preferably, the compound as described above does not include thefollowing compounds:

Advantageously, the compound of formula I is chosen among the groupcomprising:

According to a particular embodiment, an additional subject-matter ofthe present invention is a compound of formula (Ia)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a —NR₁R₂group,

R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxygroup, a —NO₂ group, a phenoxy group and a (C₁-C₄)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is preferably 1 or 2,

n′ is as defined above and is preferably 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂ group, a —COOR₁group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Id)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a (C₁-C₃)alkoxygroup,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (If)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ig)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ih)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ii)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Il)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Im)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a halogen atom or a groupchosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl group, saidalkyl being optionally mono-substituted by a hydroxyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ip)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iq)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoroalkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, aN-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a morpholino group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ir)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, amorpholino group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iee)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 2,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Among the previous defined families of compounds of formulae (Ia) to(Iee), some are more particularly preferred for their use as an agentfor preventing, inhibiting or treating AIDS. These preferred compoundsparticularly belong to formulae (Ia), (Ib), (Ic), (Ie) and (Io), asdefined above or one of its pharmaceutically acceptable salts.

Accordingly the present invention further relates to a compound offormula (Ia), (Ib), (Ic), (Ie) and (Io), as defined above, for use as anagent for preventing, inhibiting or treating AIDS.

Thus, according to a more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, ahydroxyl group, a —CN group, a —COOH group and a (C₁-C₃)alkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom, a halogen atom, a —NO₂ group or a (C₁-C₃)alkylgroup,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ia′),

wherein,

R independently represent a hydrogen atom, a —CN group, a (C₁-C₃)alkylgroup, a (C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl group,

R′ is as defined in formula (Ia) and is preferably a halogen, a(C₁-C₃)alkyl group or a NO₂ group,

R″ is a hydrogen atom,

n is 1 or 2

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom, a groupchosen among a (C₁-C₄)alkyl group, a —NR₁R₂ group, a (C₁-C₃)alkoxy groupand a (C₁-C₃)fluoroalkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above,

n′ is as defined above,

R′ is a hydrogen atom, halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ib′),

wherein:

R independently represent a hydrogen atom, a halogen atom, a groupchosen among a (C₁-C₃)alkoxy group, a (C₁-C₃)fluoroalkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ group and a(C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Io)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group and a —NO₂ group,

R″ is as defined above and more preferably is a hydrogen atom,

n is 1, 2 or 3,

n′ is as defined above,

R′ is a hydrogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating AIDS.

In a particular embodiment, the present invention relates to a compoundof formula (Ia), (Ic) or (Io) as defined above or one of itspharmaceutically acceptable salts, for use as an agent for preventing,inhibiting or treating AIDS.

According to a preferred embodiment of the present invention, thecompound for use as an agent for preventing, inhibiting or treatingAIDS, is chosen from:

-   -   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine    -   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid    -   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine    -   (4) Pyridin-2-yl-quinolin-2-yl-amine    -   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid    -   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine    -   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile    -   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine    -   (9) Pyridin-2-yl-quinolin-3-yl-amine    -   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine    -   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine    -   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine    -   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid    -   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine    -   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile    -   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (33) 2-(quinolin-2-ylamino)isonicotinonitrile    -   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (37)        8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine    -   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile    -   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid    -   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride    -   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium        chloride    -   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine    -   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine    -   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile    -   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine    -   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine    -   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine    -   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (59) methyl 6-(quinolin-2-yl amino)nicotinate    -   (60) methyl        6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (61) methyl        6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (62) methyl        2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine    -   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-di amine    -   (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine    -   (67) methyl        6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (68)        8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol    -   (70)        8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine    -   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine    -   (74)        3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (75)        4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (76) N-(4-methoxyphenyl)quinolin-2-amine    -   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine    -   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine    -   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (81)        1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine    -   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (85) N-(4-nitrophenyl)quinolin-2-amine    -   (86) N-(3-fluorophenyl)quinolin-2-amine    -   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine    -   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (91)        3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (94)        8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (95)        3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine    -   (97)        4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine    -   (102) N-(4-phenoxyphenyl)quinolin-2-amine    -   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (104)        8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine    -   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine    -   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine    -   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine    -   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine    -   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (113) N-(pyrazin-2-yl)quinolin-2-amine    -   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine    -   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine    -   (118) N-(pyridin-3-yl)quinolin-3-amine    -   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine    -   (120) N-(pyridin-4-yl)quinolin-2-amine    -   (121) N-(pyridin-4-yl)quinolin-3-amine    -   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine    -   (123) N-(4-methoxyphenyl)quinolin-3-amine    -   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (128) N-(pyrimidin-2-yl)quinolin-2-amine    -   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine    -   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine    -   (131) N-(pyrazin-2-yl)quinolin-6-amine    -   (132) N-(pyrazin-2-yl)quinolin-3-amine    -   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine    -   (134) N-(naphthalen-2-yl)pyridin-2-amine    -   (135) N-(pyridin-2-yl)quinoxalin-2-amine    -   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile    -   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine    -   (139)        N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine    -   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine    -   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine    -   (143)        4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine    -   (144)        4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine    -   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine    -   (147)        4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine    -   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine    -   (149)        5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine    -   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine    -   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (153)        6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine    -   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine    -   (156)        4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine    -   (158)        N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine    -   (159) N-(3-aminopyridin-2-yl)quinolin-3-amine    -   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine    -   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine    -   (164) [2-(quinoxalin-2-yl amino)pyridin-4-yl]methanol    -   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine    -   (166)        N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine    -   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (168)        N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine    -   and their pharmaceutically acceptable salts.

Among said compounds, compounds (1), (6), (33), (34), (35), (36), (37),(38), (42), (43), (44), (45), (46), (48), (50), (64), (68), (69), (70),(71), (72), (73), (74), (75), (77), (78), (79), (80), (81), (82), (86),(87), (88), (90), (92), (96), (104), (106), (109), (112), (136), (139),(140) and (141) are of particular interest.

The present invention therefore extends to compounds (1), (6), (33),(34), (35), (36), (37), (38), (42), (43), (44), (45), (46), (48), (50),(64), (68), (69), (70), (71), (72), (73), (74), (75), (77), (78), (79),(80), (81), (82), (86), (87), (88), (90), (92), (96), (104), (106),(109), (112), (136), (139), (140) and (141) or one of itspharmaceutically acceptable salts for use as an agent for preventing,inhibiting or treating AIDS.

Some of said preceding compounds are new and form part of the presentinvention: (1), (6), (33), (34), (35), (36), (37), (38), (42), (43),(44), (46), (48), (50), (64), (68), (69), (70), (71), (72), (73), (74),(75), (77), (78), (79), (80), (81), (82), (86), (87), (88), (90), (92),(96), (104), (106), (109), (112), (136), (139), (140), (141) and theirpharmaceutically acceptable salts, such as hydrobromide, tartrate,citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,maleate, mesylate, formate, acetate and fumarate.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Ii), (Im), (Io), (Ip), (Iq), (Ir) and (Iee) cancomprise one or more asymmetric carbon atoms. They can thus exist in theform of enantiomers or of diastereoisomers. These enantiomers,diastereoisomers and their mixtures, including the racemic mixtures, areencompassed within the scope of the present invention.

Among the compounds of formula (I), some of them are new and form partof the invention, as well as their pharmaceutically acceptable salts,such as hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate.

According to a particular embodiment, the present invention encompassescompounds of formula (Ig) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

and when n and n′ are 1 and R is a hydrogen atom then R′ is not a —COOHgroup,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (If) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ih) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Il) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Im) wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that when n and n′ are 1 and R is a hydrogen atom, R′is not a chlorine atom,

or anyone of its pharmaceutically acceptable salt.

For a sake of simplification, the following compounds and theircorresponding definitions are called “new compounds”.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ia), as such, wherein:

R″ and n are as defined in formula (Ia),

n′ is 1,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R′ is a hydrogen atom or a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,

and wherein:

with the proviso that

when R and R′ are not simultaneously a hydrogen atom,

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

when R′ is a hydrogen atom, R is not a bromine atom or a chlorine atom,

when R is a hydrogen atom, R′ is not a methyl or ethyl group, a —COOHgroup, a COOC₂H₅ group or a bromine atom, said bromine atom being inortho position of the bond linked to NR″,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia), as such,wherein,

R independently represent a hydrogen atom, a (C₁-C₃)fluoroalkyl group, ahalogen atom, a —CN group or a (C₁-C₃) alkyl group,

R″ is as defined in formula (Ia),

R′ is a hydrogen atom, a halogen atom or a —NO₂ group,

n′ is 1,

n is 1,

with the proviso that

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

R is not a bromine atom or a chlorine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore preferably focuses on compounds of formula (Ia′), as such,

wherein,

R independently represent a hydrogen atom, a (C₁-C₃) alkyl group, a(C₁-C₃)fluoroalkyl group, a halogen atom or a hydroxyl group,

R″ is as defined in formula (Ia),

n is 1 or 2, and preferably 1,

or one of its pharmaceutically acceptable salt.

The present invention further relates to a compound of formula (Ib) asdefined above, as such

wherein:

R′ and R″ are as defined in formula (Ib),

n is 1, and

R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,

-   -   or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib) wherein:

-   -   R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,    -   R′ is a hydrogen atom, a halogen atom or a (C₁-C₄)alkyl group,    -   R″ is as defined in the formula (Ib),

n′ is 1 or 2 and is preferably 1,

n is 1 or 2 and is preferably 1,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib′)

wherein:

R, R″ and n are as defined in formula (Ib),

-   -   R′ is as defined in formula (Ib),

with the proviso that R′ is different from a methyl group in position 4on the quinoline,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib″)

wherein:

-   -   R, R″ and n are as defined in formula (Ib),

with the proviso that when n is 1, R is not a hydrogen atom, a methylgroup in para of the bond linked to NR″, a ethoxy group in para of thebond linked to NR″, nor a fluorine atom in para of the bond linked toNR″,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ic), as such, wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

R is not a bromine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic), as such,wherein,

R is a hydrogen atom or a —NO₂ group,

n is 1,

R′, R″ and n′ are as defined in formula (Ic), and

R′ is preferably a (C₁-C₃)alkyl group or a hydrogen atom,

or one of its pharmaceutically acceptable salt.

The present invention further relates to a compound of formula (Ie) asdefined above, as such

wherein:

R, R′, R″ n and n′ are as defined in formula (I),

with the proviso that

when R is a hydrogen atom, R′ is not a bromine atom,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Io), as such, wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

when R is a hydrogen atom and n′ is 1, R′ is not a hydroxyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Io′), as such,wherein

wherein:

n is 1, 2 or 3,

n′ is 1 or 2,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, and is preferablya —NO₂ group, a hydrogen atom or a halogen atom,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, a (C₁-C₃)fluoroaralkylgroup, and preferably is a hydrogen atom or a (C₁-C₃)fluoroalkyl group,

R₁ and R₂ are as defined in formula (Io),

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

Among said compounds as such, compounds (1), (2), (5)-(8), (10)-(16),(18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130),(132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceuticallyacceptable salts are of particular interest.

The present invention therefore extends to compounds (1), (2), (5)-(8),(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121),(124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and theirpharmaceutically acceptable salts, as such.

More preferably, compounds (8), (75), (77)-(84), (86)-(104),(109)-(117), (155)-(158) and their pharmaceutically acceptable salts areof particular interest.

The present invention therefore extends more preferably to compounds(8), (75), (77)-(84), (86)-(104), (109)-(117), (155)-(158) and theirpharmaceutically acceptable salts, such as hydrobromide, tartrate,citrate, trifluoroacetate, ascorbate, hydrochloride, tartrate, triflate,maleate, mesylate, formate, acetate and fumarate.

Still more preferably, the present invention extends to compounds (75),(77), (78), (79), (80), (81), (82), (86), (87), (88), (90), (92), (96),(104), (109), (112), and their pharmaceutically acceptable salts, suchas hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate.

The new compounds of the present invention, i.e. compounds of formulae(Ia), (Ic), (Io), (Ib), (Ib), (Ib″) and (Ie) and the specific compoundsas listed above, are not only useful as agent for inhibiting, preventingor treating AIDS but can also be useful for inhibiting, preventing ortreating premature aging and for inhibiting, preventing or treatingcancer, and more particularly colorectal cancer, pancreatic cancer, lungcancer including non-small cell lung cancer, breast cancer, bladdercancer, gall bladder cancer, liver cancer, thyroid cancer, melanoma,uterine/cervical cancer, oesophageal cancer, kidney cancer, ovariancancer, prostate cancer, head and neck cancer and stomach cancer, etc.

According to an aspect of the invention said compounds may be useful toinhibit, prevent and/or treat diseases with premature aging and that arelikely related to an aberrant splicing of the nuclear lamin A gene.Among all, said disease may include Hutchinson Guilford ProgeriaSyndrome (HGPS), progeria, premature aging associated with HIVinfection, muscular dystrophy, Charcot-Marie-Tooth disorder, Wernersyndrome, but also atherosclerosis, insulin resistant type II diabetes,cataracts, osteoporosis and aging of the skin such as restrictivedermopathy.

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below represent a general methoduseful for preparing the compounds of the present invention and are notmeant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 (above, See EMBODIMENT I). The chemical structures and spectroscopicdata of some compounds of formula (I) of the invention are illustratedrespectively in the following Table I (above) and Table II (above).

The following examples are provided as illustrations and in no way limitthe scope of this invention.

The following examples illustrate in detail the preparation of somecompounds according to the invention. The structures of the productsobtained have been confirmed by NMR spectra.

Embodiment II: Examples

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a 1.1 molar ratio with respect to the compound of formula(III) in presence of Cs₂CO₃, in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), in a 2 mol %amount relative to the total amount of compound of formula (III), and inthe presence of Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (III). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compounds (6), (43), (77),(80), (90), (112) and (136).

According to route (B), the compound of formula (V) is placed in aprotic solvent such as tert-butanol. The compound of formula (VI) isthen added in a 1.1 molar ratio with respect to the compound of formula(V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %amount relative to the total amount of compound of formula (V), and inthe presence of a Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (V). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compound (106).

Example 1: Compound (6) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (1.5 g) and2-amino-4methylpyridine (904 mg), Pd(OAc)₂ (34 mg), XantPhos (88 mg) andCs₂CO₃ (7.0 g) in 30 mL of t-BuOH gave compound (6) (1.3 g).

¹H NMR (300 MHz, DMSO) δ 10.23 (s, 1H), 8.96 (s, 1H), 8.18 (d, J=8.8,2H), 7.78 (dd, J=7.7, 13.7, 2H), 7.46 (d, J=8.9, 1H), 7.31 (t, J=7.8,1H), 6.86 (d, J=4.3, 1H), 2.37 (s, 3H).

¹³C NMR (75 MHz, DMSO) δ 153.63, 153.61, 148.37, 147.32, 142.65, 137.52,129.68, 129.47, 126.82, 125.06, 123.26, 118.36, 115.10, 113.31, 21.24.

MS (ESI) [M+H]⁺=270

Example 2: Compound (43) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (394 mg) and2-amino-5fluoropyridine (246 mg), Pd(OAc)₂ (9 mg), XantPhos (23 mg) andCs₂CO₃ (1.8 g) in 8 mL of t-BuOH gave compound (43) (320 mg).

¹H NMR (300 MHz, DMSO) δ 10.41 (s, 1H), 9.08 (dd, J=4.1, 9.3, 1H), 8.31(d, J=2.9, 1H), 8.20 (d, J=8.9, 1H), 7.88-7.70 (m, 3H), 7.44 (d, J=8.9,1H), 7.32 (t, J=7.8, 1H).

¹³C NMR (75 MHz, DMSO) δ 156.30, 153.32, 153.04, 150.17, 142.55, 137.73,135.06, 134.74, 129.58, 129.49, 126.86, 125.29, 125.14, 125.04, 123.36,114.91, 113.36.

MS (ESI) [M+H]⁺=274

Example 3: Compound (77) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (985 mg) andp-anisidine (677 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) and Cs₂CO₃ (4.6g) in 20 mL of t-BuOH gave compound (77) (629 mg).

¹H NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.8, 1H), 7.70 (d, J=7.6, 1H), 7.59(d, J=8.6, 2H), 7.52 (d, J=7.3, 1H), 7.16 (t, J=7.7, 1H), 6.94 (d,J=8.4, 3H), 6.86 (d, J=8.8, 1H), 3.82 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 156.40, 155.54, 144.29, 138.09, 132.96,130.44, 129.99, 126.61, 125.22, 123.29, 122.66, 114.73, 112.16, 55.74.

MS (ESI) [M+H]⁺=285

Ample 4: Compound (80) of the Table I

According to route (A), a mixture of 2-chloro-3methylquinoline (885 mg)and 4-(trifluoromethoxy)aniline (743 μL), Pd(OAc)₂ (22 mg), XantPhos (58mg) and Cs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (80) (1.3 g).

¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.9 Hz, 2H), 7.84 (d, J=8.3 Hz,1H), 7.78 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 7.32(t, J=7.4 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.53 (s, 1H), 2.42 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 152.46, 146.25, 143.86, 139.33, 136.83,128.93, 126.96, 126.71, 124.75, 123.56, 121.88, 120.44, 119.95, 17.77.

MS (ESI) [M+H]⁺=319

Example 5: Compound (90) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (984 mg) and4-(trifluoromethoxy)aniline (743 μL), Pd(OAc)₂ (22 mg), XantPhos (58 mg)and Cs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (90) (1.1 g).

¹H NMR (300 MHz, CDCl₃) δ 7.84 (d, J=9.1, 2H), 7.79 (d, J=8.9, 1H), 7.67(dd, J=1.2, 7.6, 1H), 7.48 (dd, J=1.1, 8.0, 1H), 7.18 (s, 3H), 6.89 (s,1H), 6.75 (d, J=8.9, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 153.88, 144.30, 143.91, 139.00, 138.25,131.13, 130.13, 126.55, 125.42, 123.45, 122.50, 122.17, 120.49, 119.10,113.24.

MS (ESI) [M+H]⁺=339

Example 6: Compound (106) of the Table I

According to route (B), a mixture of 3-aminoquinoline (316 mg) and2-chloro-3nitropyridine (315 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) andCs₂CO₃ (4.6 g) in 20 mL of t-BuOH gave compound (106) (374.1 mg).

¹H NMR (300 MHz, DMSO) δ 10.24 (s, 1H), 9.06 (d, J=2.3, 1H), 8.65 (d,J=1.8, 1H), 8.60 (d, J=8.3, 1H), 8.56 (d, J=4.5, 1H), 7.97 (dd, J=8.2,14.4, 2H), 7.69 (t, J=6.9, 1H), 7.59 (t, J=7.4, 1H), 7.08 (dd, J=4.6,8.3, 1H).

MS (ESI) [M+H]⁺=267

Example 7: Compound (112) of the Table I

According to route (A), a mixture of 2,8-dichloroquinoline (958 mg) andaminopyrazine (522 mg), Pd(OAc)₂ (22 mg), XantPhos (58 mg) and Cs₂CO₃(4.6 g) in 20 mL of t-BuOH gave compound (112) (728 mg).

¹H NMR (300 MHz, DMSO) δ 10.58 (s, 1H), 10.26 (s, 1H), 8.36 (s, 1H),8.27 (s, 2H), 7.91-7.74 (m, 2H), 7.50 (d, J=8.8, 1H), 7.37 (t, J=7.6,1H).

¹³C NMR (75 MHz, DMSO) δ 152.94, 150.19, 142.48, 142.18, 138.20, 137.55,135.74, 129.71, 126.99, 125.35, 123.84, 114.75.

MS (ESI) [M+H]⁺=255

Example 7: Compound (136) of the Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg) and2-amino-4methylpyridine (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (136) (35.4 mg).

¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 8.70 (s, 1H), 8.30 (s, 1H), 8.20(d, J=5.1, 1H), 7.94 (d, J=8.1, 1H), 7.84 (d, J=8.2, 1H), 7.64 (t,J=7.6, 1H), 7.49 (t, J=8.1, 1H), 6.83 (d, J=5.0, 1H), 2.43 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 153.28, 150.20, 148.55, 147.40, 140.93,139.83, 138.35, 130.44, 129.16, 127.18, 126.28, 119.70, 113.75, 21.87.

MS (ESI) [M+H]⁺=237

Example 8: Method for Synthesizing the Compounds of the PresentInvention

Typical Procedure for Pd-Catalysed Aminations

To a solution of halogeno compound (0.5 mmol, 1 equiv) in tert-butanol(2 mL) were added the amino moiety (0.55 mmol, 1.1 equiv), Cs₂CO₃ (456mg, 1.4 mmol, 2.8 equiv), Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) (5.8 mg, 0.01 mmol, 2mol %), Pd(OAc)₂ (2.2 mg, 0.01 mmol, 2 mol %). The reaction mixture washeated at 90° C. and stirred for 20 h under argon. The reaction mixturewas concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel to yield pure compounds.

For example this procedure permitted to synthesize the followingcompounds:

Isoquinolin-5-yl-(3-methoxy-pyridin-2-yl)-amine

¹H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 8.66 (dd, J=1.7, 6.8, 1H), 8.55(d, J=6.0, 1H), 7.85 (d, J=5.0, 1H), 7.76 (d, J=6.0, 1H), 7.69-7.58 (m,2H), 7.53 (s, 1H), 7.06 (d, J=7.7, 1H), 6.78 (dd, J=5.1, 7.8, 1H), 3.99(s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 153.23, 146.60, 142.97, 142.79, 138.53,134.82, 129.53, 129.13, 127.95, 121.66, 119.82, 115.18, 115.05, 114.09,100.15, 55.80.

(8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine: (6) of the TableI

¹H NMR (300 MHz, CDCl3) δ 8.82 (s, 1H), 8.17 (d, J=5.1, 1H), 8.09 (s,1H), 7.98 (d, J=8.9, 1H), 7.76 (dd, J=1.2, 7.6, 1H), 7.61 (dd, J=1.0,8.0, 1H), 7.26 (t, J=7.8, 2H), 7.15 (d, J=8.7, 1H), 6.83 (d, J=5.0, 1H),2.46 (s, 3H).

¹³C NMR (75 MHz, CDCl3) δ 153.52, 153.14, 149.90, 147.43, 143.68,138.08, 131.37, 129.98, 126.56, 125.58, 123.58, 119.17, 114.52, 114.02,21.84.

(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine: (10) of the Table I

¹H NMR (300 MHz, DMSO) δ 9.17 (d, J=2.5, 1H), 8.97 (d, J=2.4, 1H), 8.79(s, 1H), 7.94-7.79 (m, 3H), 7.58-7.46 (m, 2H), 7.31 (d, J=7.9, 1H), 6.88(dd, J=5.0, 7.9, 1H), 3.94 (s, 3H).

Pharmacological Data

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treating AIDS.

Example 9: Development of IDC16 Derivative Compounds

The inventors have shown that compound IDC16 (BAKKOUR et al., citedabove, 2007) interacts functionally with the SF2/ASF complex and thuscontributes to blocking alternative splicing during HIV replication,leading to the termination of the production of Tat protein.

Accordingly, the family of polycyclic indoles, to which compound IDC16belongs, is known to exhibit the properties of DNA intercalating agents.Such compounds thus present a risk in terms of undesirable side effects.

The inventors thus sought to develop novel molecules exhibiting activitycomparable to IDC16, in terms of activity inhibiting HIV splicing, butwhile not exhibiting the characteristics of DNA intercalating agents.

In their initial hypothesis, the inventors considered that the two polarheterocycles at the two ends of compound IDC16 were associated with itsactivity and that the two median rings were of less importance.

Based on this hypothesis, the inventors considered that:

-   -   the nitrogen of the indoline and of the D ring of IDC16 might        act as acceptors of hydrogen bonds;    -   the N-methylated 4-pyridinone motif might be preserved in the        analogues;    -   the flat tetracyclic geometry was not optimal and it might be        wise to replace the B and C rings by other motifs to limit DNA        intercalating properties.

Example 10: Inhibition of HIV-1 Production in Infected Peripheral BloodMononuclear Cells (PBMCs)

Material and Methods

The first determination is that of the concentration of compound thatexhibits the fewest side effects in terms of cell viability andprogression of the cell cycle.

Within this framework, the peripheral blood mononuclear cells (PBMCs) ofhealthy donors are isolated by centrifugation on a FICOLL gradient. Thecells are then cultivated to a density of 2.5×10⁶ cells/ml with RPMImedium supplemented with 1% inactivated human AB serum, then incubatedat 37° C., 5% CO₂ for an additional hour. The peripheral bloodmononuclear cells are then recovered and cultivated for two days in RPMImedium supplemented with 10% fetal calf serum.

A standard experiment using 96 plates to test 30 molecules intriplicates including positive and negative controls, is performed asfollows:

50 10⁶ Ficoll purified PBMCs (10% DMSO 90% FCS) are washed with RPMI 10%FCS and resuspended in 25 ml of RPMI 10% FCS, glutamax containing 1000U/ml of IL2 and 5 μg/ml PHA. The cells are then incubated for 3 days at37° C. before to be washed with 50 ml PBS then with 50 ml RPMI 10% FCS.The cells are resuspended in 100 μl of RPMI 10% FCS containing 100 U/mlIL2 and seeded in 96 wells (1.5 10⁵ cells/well). Viral infection isperformed with 1 ng of AdaM/well. 100 μl of tested molecules atconcentration of 10 μM are added to each well. Virus production isdetermined by p24 antigen immunosorbent assays after 3 and 6 days ofinfection (Kit Innogenetics). Typically PBMCs are prepared from severalhealthy donors (around 11 different donors). Dose response curves werethen established with selected compounds to determine IC₅₀.

Protocol for Cytotoxicity:

To evaluate the cytoxicity of different compounds we used the sameprotocol as above to seed the HOS-CD4⁺-CCR5⁺ cells or PBMCs in a finalvolume of 100 μl without adding the virus. After an incubation for 48 hat 37° C., the medium was removed and cells were incubated with 20 μl ofCellTiter96 AqueousOne solution to determine the number of viable cellsin proliferation and cytotoxicity assays (Promega). CellTiter96AqueousOne is a colorimetric assay solution that has many advantagescompared to MTT assays and gives us satisfactory results.

We have also evaluated the effect of selected molecules on CD4 and CD8proliferation using the division tracking dye carboxyfluoresceindiacetate succinimidyl ester (CFSE) (In vitrogen).

Results

Inhibition of p24 production in HIV infected PBMCs from Compound numberIC₅₀ in nM different donors Formula (Ia) 1 nd 4 out 6 donnors 6 0.1 9out 14 donnors  33 nd 5 out 6 donnors 34 nd 6 out 8 donnors 35 nd 6 out8 donnors 36 nd 6 out 8 donnors 37 nd 4 out 6 donnors 38 nd 4 out 6donnors 42 nd 4 out 6 donnors 43 0.1  8 out of 10 donnors 44 nd 4 out 6donnors 45 nd 4 out of 4 donnors 46 nd 4 out of 4 donnors 48 nd 4 out 4donnors 50 nd 4 out of 4 donnors 64 nd 5 out of 5 donnors 68 nd 4 out of4 donnors 69 nd 4 out of 4 donnors 70 nd 4 out of 4 donnors 71 nd 4 outof 4 donnors 72 nd 4 out of 4 donnors 73 nd 4 out of 4 donnors 74 nd 4out of 4 donnors Formula (Ib) 75 nd 6 out of 7 donnors 77  0.05 11 outof 13 donnors 78 nd 7 out of 8 donnors 79 nd 7 out of 8 donnors 80 1   7out of 8 donnors 81 nd 4 out of 4 donnors 82 nd 4 out of 4 donnors 86 nd3 out of 4 donnors 87 nd 4 out of 4 donnors 88 nd 4 out of 4 donnors 900.1  8 out of 10 donnors 92 nd 3 out of 5 donnors 96 nd 5 out of 6donnors 104 nd 4 out of 4 donnors Formula (Ic) 106 0.5 6 out of 6donnors Formula (Ie) 109 nd 8 out of 8 donnors 112 0.1 12 out of 13donnors Formula (Io) 136 nd 6 out of 8 donnors 139 nd 4 out of 4 donnors140 nd 4 out of 4 donnors 141 nd 4 out of 4 donnors

Example 11: Inhibition of HIV-1 Production in Infected Macrophages

In order to generalize the HIV-1 replication effect of the molecules ofthe present invention to other cell types, we examined various steps ofthe viral cycle in cells treated with the various drug at aconcentration of 5 μM and submitted to one-round infection.

For such experiences, macrophages can be infected by the Ada-M R5 HIVstrain and treated for 18 hours with various concentrations of thecompounds of the present invention. The culture medium is theneliminated and the cells washed with an abundance of PBS. The cells arethen cultivated under normal conditions. The culture medium and thecells are then collected at days 4, 7 and 14. Finally, virus replicationis measured indirectly by determining the level of p24 antigen in boththe culture supernatant and the cellular lysate by the ELISA method. Inparallel, cell viability of the macrophages in the presence of thecompounds of the present invention is measured as before.

For this purpose, we exposed HOS-CD4⁺-CCR5⁺ cells to defective virionsobtained by cotransfecting 293T cells with a plasmid encoding the R5envelope of the AD8 strain and another plasmid containing the entireHIV-1 genome mutated in the envelope gene and harbouring a luciferasemarker gene fused to nef (Connor R I, Chen B K, Choe S, Landau N R.(1995) Vpr is required for efficient replication of humanimmunodeficiency virus type-1 in mononuclear phagocytes. Virology 206:935-944.). The amounts of luciferase activity in cells infected withthese virions reflect both the number of integrated proviruses andexpression of multiply spliced species encoding nef/luc. Two dayspost-infection, luciferase activity in HOS-CD4+-CCR5+ infected cells wasmeasured.

The results are shown below:

Compound Results

+

−

+

−

+

−

−

−

−

+

−

The results established that the compounds of the present invention showa luciferase inhibitory effect, thus showing that these compoundsinhibit viral RNA splicing.

A further object of the invention consists of a pharmaceuticalcomposition comprising at least one compound of formula (Ib) or (Ie) oranyone of compounds (8), (75), (77)-(84), (86)-(104), (109)-(117),(155)-(158) and their pharmaceutically acceptable salts, such ashydrobromide, tartrate, citrate, trifluoroacetate, ascorbate,hydrochloride, tartrate, triflate, maleate, mesylate, formate, acetateand fumarate and, optionally, a pharmaceutically acceptable support.

As examples of pharmaceutically acceptable supports, the composition caninclude emulsions, microemulsions, oil in water emulsions, anhydrouslipids and water in oil emulsions or other types of emulsions.

The inventive composition can further include one or more additives suchas diluents, excipients, stabilizers and preservatives. Such additivesare well known to those skilled in the art and are described notably in“Ullmann's Encyclopedia of Industrial Chemistry, 6^(th) Ed.” (variouseditors, 1989-1998, Marcel Dekker) and in “Pharmaceutical Dosage Formsand Drug Delivery Systems” (ANSEL et al., 1994, WILLIAMS & WILKINS).

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

In this context they can be present in any pharmaceutical form which issuitable for enteral or parenteral administration, in association withappropriate excipients, for example in the form of plain or coatedtablets, hard gelatine, soft shell capsules and other capsules,suppositories, or drinkable, such as suspensions, syrups, or injectablesolutions or suspensions, in doses which enable the daily administrationof from 0.1 to 1000 mg of active substance.

Still a further object consists of the use of at least one compound offormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above, andcompounds (1) to (168) as defined above, or one of its pharmaceuticallyacceptable salts according to the present invention in preparing a drugto treat, in a subject, a disease resulting from at least one splicinganomaly.

Therefore, the present invention relates to a compound of formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),(Im), (Io), (Ip), (Iq), (Ir) or (Iee) as defined above, and compounds(1) to (168) as defined above, or one of its pharmaceutically acceptablesalts according to the present invention for preparing a drug to treat,in a subject, a disease resulting from at least one splicing anomaly.

As used in the present application, the term “subject” refers to amammal such as a rodent, cat, dog, primate or human, preferably saidsubject is a human.

Preferably, the inventive compounds have the ability to inhibitpre-messenger RNA splicing processes that are either constitutive or,more specifically, dependent on regulating sequences known as an ESE(exonic splicing enhancer), ISE (intronic splicing enhancer), ESS(exonic splicing silencer) and ISS (intronic splicing silencer).

In a particularly preferred way, splicing processes are eitherconstitutive and/or or dependent on ESE regulating sequences.

Preferably, the present invention relates to the use of the at least onecompound of formula (I), (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) or (Iee) asdefined above, or one of its pharmaceutically acceptable salts accordingto the present invention, and more particularly of formula (Ia), (Ib),(Ic), (Ie) and (Io) as described above for preparing a drug to treat, ina subject, AIDS.

Therefore, the present invention relates to a one of said compounds, andmore particularly to a compound (1) to (168) or one of its acceptablesalts for treating AIDS.

Another object of the invention relates to a therapeutic method fortreating a subject for a genetic disease resulting from splicinganomalies comprising the administration of a therapeutically effectivequantity of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir)or (Iee) as defined above, more particularly of formula (Ia), (Ib),(Ic), (Ie) and (Io) as described above, and even more particularly of atleast one compound (1) to (168) or one of its acceptable salts.

Preferably, said genetic disease resulting from splicing anomalies isAIDS.

A “therapeutically effective quantity” means a quantity that inducesinhibition of the splicing of the pre-mRNAs of interest. Those skilledin the art will be able to determine said therapeutically effectivequantity based on their general knowledge and on the methods describedin the examples.

The compounds can be administered by any mode of administration such as,for example, by intramuscular, intravenous or oral route, etc.

In one embodiment according to the invention, said composition furtherincludes an excipient making it possible to formulate the inventivecompounds in such a way that said composition is provided in solid orliquid form to be prepared and administered by intravenous route.

The inventive compounds preferably will be administered by intravenousroute at a concentration of 80-100 mg/m². The concentration will bechosen by those skilled in the art according to the organ or tissue tobe treated, the state of advancement of the disease and the targetingmode used.

Embodiment III (Premature Aging)

The present invention of EMBODIMENT III is based on a novel approachbased on the inhibition of aberrant splicing leading to progerinproduction.

The truncated Lamin A protein lacking the last 150 base pairs of exon 11also called “progerin”, acting as a dominant negative mutant, ispredicted to be responsible for the characteristic manifestations seenin HGPS patients. Given that similar alteration of lamin A/C splicingwas observed in aged individuals, it is proposed here that therapeuticmolecules that interfere with the usage of the cryptic splice site willprevent side effects associated with accumulation of progerin duringphysiological aging. In other words, the compounds according to thepresent invention prevent usage of the cryptic 5′ splice site in exon 11of LMNA, allowing overcoming deleterious effect associated withprogerin.

According to a first aspect, a subject-matter of the present inventionrelates to a compound of formula (I)

-   -   wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, a (C₁-C₄)alkoxy group, a phenoxy group and a (C₁-C₃)alkylgroup, said alkyl being optionally mono-substituted by a hydroxyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a morpholinyl or a morpholino group, a N-methylpiperazinyl group,a (C₁-C₃)fluoroalkyl group, a (C₁-C₄)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

T is N or C,

U is N or C,

and wherein at most four of the groups V, T, U, Z, Y, X and W are N,

and at least one of the groups T, U, Y, X and W is N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a particular embodiment, the present invention furtherrelates to compounds of formula (I′)

-   -   wherein:

means an aromatic ring wherein V is C or N and when V is N, V is inortho, meta or para of Z, i.e. forms respectively a pyridazine, apyrimidine or a pyrazine group,

R independently represents a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

Z is N or C,

Y is N or C,

X is N or C,

W is N or C,

and wherein at most two of the groups V, Z, Y, X and W are N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to one aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein V is N, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to one aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is N, X is C and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is C, V is C, Y is N, X is C and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is C, X is N and W is C, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect of this particular embodiment, the presentinvention relates to a compound of formula (I′) as defined above,wherein Z is N, V is C, Y is C, X is C and W is N, for use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C andW is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is Cand W is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is Nand W is C, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is Cand W is N, for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

In one particular variant, the present invention is directed to acompound of formula (I) wherein:

Z is N or C, Y is N or C, X is N or C and W is C,

n is equal to 1,

R is a hydrogen atom, a —COOH group, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkoxy group,

R′ is a hydrogen atom,

R″ is a hydrogen atom, and

wherein at most two of the groups Z, Y and X are N,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Still in another particular variant, the compound of formula (I) may bedefined as a compound of formula (IIa) as follows:

wherein:

Z is N or C, Y is N or C, X is N or C,

at least one of R₃ and R₄ is a hydrogen atom and the other is a —COOHgroup, a (C₁-C₃)alkyl group or a (C₁-C₃)fluoroalkoxy group, or anyone ofits pharmaceutically acceptable salt.

Therefore, the present invention extends to a compound of formula (IIa)as defined above for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

The present invention further relates to a compound of formula (IIb)

wherein:

Y is N or C,

X is N or C,

R₅ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —CN group, a (C₁-C₃)alkoxy group, a —NO₂ group anda (C₁-C₃)fluoroalkyl group, and

R′ and R″ are as defined above,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (IIc)

-   -   wherein:

Y is N or C,

X is N or C,

R₅ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —CN group, a (C₁-C₃)alkoxy group, a —NO₂ group anda (C₁-C₃)fluoroalkyl group, and

R′ and R″ are as defined above,

or anyone of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a first particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ia-1)

-   -   wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group anda (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is 1 or 2, and advantageously 1, and

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (Ia-1) asdefined above, as such,

wherein:

R, R″ and n are as defined above,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a —COOH group and a —CN group, and

wherein R and R′ are not simultaneously a hydrogen atom or a methylgroup and R is not a bromine atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia′-1)

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a hydrogenatom, a —COOH group or a (C₁-C₃)alkyl group, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a second particular embodiment, an additionalsubject-matter of the present invention is a compound of formula (Ib-1)

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxy group, a —COOH group and a —CN group, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The present invention further relates to a compound of formula (Ib-1) asdefined above, as such

wherein:

R′ and R″ are as defined above,

n is 1, and

R is a (C₁-C₃)fluoroalkoxy group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ib′-1)

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a(C₁-C₃)fluoroalkoxy group or a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a third particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic-1)

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

n is 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group, and in particular is ahydrogen atom, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

The present invention further relates to a compound of formula (Ic-1) asdefined above, as such

wherein:

R, R′ R″ and n are as defined above, and

wherein R and R′ are not simultaneously a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic′-1):

wherein:

at least one of R₃ and R₄ is a hydrogen atom and the other is a(C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to a fourth particular embodiment, an additionalsubject-matter of the present invention is a compound of formula (Id-1):

wherein:

R independently represent a hydrogen atom, a halogen atom, or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOH group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group and a —NO₂ group,

n is 1 or 2, and advantageously 1,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group, and in particular is ahydrogen atom, and

R″ is as defined above and is advantageously a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

The compound of formula (Id-1) as such and as defined above also formpart of the present invention, with the proviso that when R′ is ahydrogen atom, R is different from a —NO₂ group, or one of itspharmaceutically acceptable salt.

The compounds of formulae (I′), (IIa), (IIb), (IIc), (Ia-1), (Ib-1),(Ic-1) and (Id-1) can comprise one or more asymmetric carbon atoms. Theycan thus exist in the form of enantiomers or of diastereoisomers. Theseenantiomers, diastereoisomers and their mixtures, including the racemicmixtures, are encompassed within the scope of the present invention.

According to one aspect, the present invention relates to a compound offormula (I) as defined above, wherein Z is N, V is C, Y is N, X is C, Tis C, U is C and W is C, for use as an agent for preventing, inhibitingor treating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is C,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is C and W is N, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is N, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is N and is in metaof Z and is in para of the bond linked to NR″, Y is C, X is N, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and in ortho of the bond linked to NR″, Y is N, X is C, T is C, Uis C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in paraof Z, Y is C, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is N, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is N and is in metaof Z and is in ortho of the bond linked to NR″, Y is N, X is N, T is C,U is C and W is C, for use as an agent for preventing, inhibiting ortreating pathological or nonpathological conditions linked withpremature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is N, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is N, V is C, Y is C, X is C,T is C, U is N and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

The compounds of the invention may exist in the form of free bases or ofaddition salts with pharmaceutically acceptable acids.

Suitable physiologically acceptable acid addition salts of compounds offormula (I) include hydrochloride, hydrobromide, tartrate, fumarate,citrate, trifluoroacetate, ascorbate, triflate, mesylate, tosylate,formate, acetate and malate.

The compounds of formula (I) and or salts thereof may form solvates(e.g. hydrates) and the invention includes all such solvates.

In the context of EMBODIMENT IIII of the present disclosure, the term:

-   -   “halogen” is understood to mean chlorine, fluorine, bromine, or        iodine, and in particular denotes chlorine, fluorine or bromine,    -   “(C₁-C₃)alkyl” as used herein respectively refers to C₁-C₃        normal, secondary or tertiary saturated hydrocarbon. Examples        are, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl,    -   “(C₁-C₃)alkoxy” as used herein respectively refers to        O—(C₁-C₃)alkyl moiety, wherein alkyl is as defined above.        Examples are, but are not limited to, methoxy, ethoxy,        1-propoxy, 2-propoxy,    -   “fluoroalkyl group” and “fluoroalkoxy group” refers respectively        to alkyl group and alkoxy group as above-defined, said groups        being substituted by at least one fluorine atom. Examples are        perfluoroalkyl groups, such as trifluoromethyl or        perfluoropropyl, and    -   “patient” may extend to humans or mammals, such as cats or dogs.

According to one embodiment, the present invention relates to a compoundof formula (I) as defined above for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging, wherein T is C, and Z, V, Y, X, U and W are asdefined above.

According to another embodiment, the present invention relates to acompound of formula (I) as defined above for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging, wherein W is C, and Z, V, Y, X,U and T are as defined above.

According to another embodiment, the present invention relates to acompound of formula (I) as defined above for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging, wherein Z is N, V is C, U is C,T is C and W, Y and X are as defined above.

According to one preferred aspect, the present invention relates to acompound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is C, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is C, T is C, U is C and W is N, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in para of Z, Y is N, X is C, T is C, U is C and W is C, for use asan agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

According to another aspect, the present invention relates to a compoundof formula (I) as defined above, wherein Z is C, V is C, Y is C, X is N,T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is C, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in meta of Z and is in ortho of the bond linked to NR″, Y is N, X isC, T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isN, X is N, T is C, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is N andis in meta of Z and is in ortho of the bond linked to NR″, Y is N, X isN, T is C, U is C and W is C, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to another preferred aspect, the present invention relates toa compound of formula (I) as defined above, wherein Z is N, V is C, Y isC, X is C, T is N, U is C and W is C, for use as an agent forpreventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging.

According to a particular embodiment, an additional subject-matter ofthe present invention is a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group, a (C₁-C₃)alkoxy group and a —NR₁R₂group,

R₁ and R₂ are a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —NR₁R₂ group, a (C₁-C₃)fluoroalkoxygroup, a —NO₂ group, a phenoxy group and a (C₁-C₄)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is preferably 1 or 2,

n′ is as defined above and is preferably 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₄)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —NR₁R₂ group, a —COOR₁group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Id)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group and a (C₁-C₃)alkoxygroup,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a group chosen among a(C₁-C₃)alkyl group and a (C₁-C₃)alkoxy group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (If)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ig)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ih)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ii)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ij)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Il)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Im)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a halogen atom or a groupchosen among, a —NO₂ group, a —CN group and a (C₁-C₃)alkyl group, saidalkyl being optionally mono-substituted by a hydroxyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)fluoroalkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ip)

wherein:

R represents a hydrogen atom,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iq)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoroalkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, aN-methylpiperazinyl group, a (C₁-C₃)alkoxy group and a morpholino group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Ir)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 1,

R′ is a hydrogen atom or a group chosen among a —NR₁R₂ group, amorpholino group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another particular embodiment, an additional subject-matterof the present invention is a compound of formula (Iee)

wherein:

R independently represent a hydrogen atom, a (C₁-C₃)alkyl group or a(C₁-C₃)fluoroalkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above and is advantageously 2,

R′ is a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Among the previous defined families of compounds of formulae (Ia) to(Iee), some are more particularly preferred for their use as an agentfor preventing, inhibiting or treating pathological or nonpathologicalconditions linked with premature aging. These preferred compoundsparticularly belong to formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ii),(Ij), (Ik), (Io), (Ip) and (Ir), as defined above or one of itspharmaceutically acceptable salts.

Accordingly the present invention further relates to a compound chosenamong compounds of formulae (Ia), (Ib), (Ic), (Id), (Ie), (Ii), (Ij),(Ik), (Io), (Ip), (Ir) and their pharmaceutically acceptable salts foruse as an agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

Furthermore, among such compounds particularly preferred for their useas described above, some of them, i.e. compounds of formulae (Ia), (Ib),(Ic), (Ie), (Ii), (Ij), (Ik), and (Io) are more particularly preferredfor their use, as described below:

Thus, according to a more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ia)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above and more preferably is 1,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

Still according to this more particular embodiment, the presentinvention more preferably focuses on compounds of formula (Ia′),

wherein,

R independently represent a hydrogen atom, a —COOR₁ group or a (C₁-C₃)alkyl group,

R₁ is as defined above,

R″ is a hydrogen atom,

n is 1 or 2,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ib)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkoxy group and aphenoxy group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ic)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group, a —NO₂ group and a (C₁-C₃)alkoxy group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ie)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom or a halogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ii)

wherein:

R independently represent a hydrogen atom or a (C₁-C₃)alkoxy group,

R″ is as defined above and is advantageously a hydrogen atom,

n is as defined above and is advantageously 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ij)

wherein:

-   -   R independently represent a hydrogen atom or a group chosen        among a (C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkyl group,    -   R″ is as defined above and more preferably is a hydrogen atom,    -   n is as defined above and more preferably is 2,    -   n′ is as defined above,    -   R′ is a hydrogen atom,    -   or one of its pharmaceutically acceptable salt,        for use as an agent for preventing, inhibiting or treating        pathological or nonpathological conditions linked with premature        aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Ik)

wherein:

R represents a hydrogen atom,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

According to another more particular embodiment, the present inventionparticularly focuses on a compound of formula (Io)

wherein:

R independently represent a hydrogen atom or a group chosen among a(C₁-C₃)alkyl group and a —CN group,

R″ is as defined above and more preferably is a hydrogen atom,

n is as defined above and more preferably is 1,

n′ is as defined above,

R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt,

for use as an agent for preventing, inhibiting or treating pathologicalor nonpathological conditions linked with premature aging.

In a particular embodiment, the present invention relates to a compoundof formula (Ib), (Ie) or (Ij) as defined above or one of itspharmaceutically acceptable salts, for use as an agent for preventing,inhibiting or treating pathological or nonpathological conditions linkedwith premature aging.

According to a preferred embodiment of the present invention, thecompound for use as an agent for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging,is chosen from:

-   -   (1) (8-Chloro-quinolin-2-yl)-pyridin-2-yl-amine    -   (2) 2-(Quinolin-2-ylamino)-isonicotinic acid    -   (3) (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine    -   (4) Pyridin-2-yl-quinolin-2-yl-amine    -   (5) 2-(8-Chloro-quinolin-2-ylamino)-isonicotinic acid    -   (6) (8-Chloro-quinolin-2-yl)-(4-methyl-pyridin-2-yl)-amine    -   (7) 6-(Quinolin-2-ylamino)-nicotinonitrile    -   (8) Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine    -   (9) Pyridin-2-yl-quinolin-3-yl-amine    -   (10) (3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine    -   (11) Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (12) (5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine,    -   (13) (5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine    -   (14) 2-(Quinolin-3-ylamino)-isonicotinic acid    -   (15) Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine    -   (16) (6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine    -   (17) N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (18) 8-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (19) 4-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (20) 4-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (21) 3-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (22) 3-methyl-N-(pyridin-2-yl)quinolin-2-amine    -   (23) 6-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (24) 6-((3-methylquinolin-2-yl)amino)nicotinonitrile    -   (25) 6-chloro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (26) 6-chloro-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (27) 4-methyl-N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (28) N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (29) 8-chloro-N-(3-nitropyridin-2-yl)quinolin-2-amine    -   (30) 2-((4-methylquinolin-2-yl)amino)nicotinonitrile    -   (31) N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (32) N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (33) 2-(quinolin-2-yl amino)isonicotinonitrile    -   (34) N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (35) 8-chloro-N-(3-methylpyridin-2-yl)quinolin-2-amine    -   (36) 8-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (37)        8-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (38) N-(3-methoxypyridin-2-yl)quinolin-2-amine    -   (39) N-(5-nitropyridin-2-yl)quinolin-2-amine    -   (40) 6-((8-chloroquinolin-2-yl)amino)nicotinonitrile    -   (41) N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (42) N-(6-(trifluoromethyl)pyridin-2-yl)quinolin-2-amine    -   (43) 8-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (44) 2-((8-chloroquinolin-2-yl)amino)nicotinic acid    -   (45) 4-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (46) 3-methyl-N-(6-methylpyridin-2-yl)quinolin-2-amine    -   (47) 5-cyano-2-(quinolin-2-ylamino)pyridin-1-ium chloride    -   (48) 2-((8-chloroquinolin-2-yl)amino)-4-methylpyridin-1-ium        chloride    -   (49) 8-chloro-N-(4-ethylpyridin-2-yl)quinolin-2-amine    -   (50) 8-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (51) 8-chloro-N-(4,6-dimethylpyridin-2-yl)quinolin-2-amine    -   (52) 6-((8-chloroquinolin-2-yl)amino)-2-methylnicotinonitrile    -   (53) 8-chloro-N-(4-chloropyridin-2-yl)quinolin-2-amine    -   (54) 8-methyl-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (55) N-(5-bromo-4-methylpyridin-2-yl)-8-chloroquinolin-2-amine    -   (56) 8-chloro-N-(3-ethyl-6-methylpyridin-2-yl)quinolin-2-amine    -   (57) 8-fluoro-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (58) 8-bromo-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (59) methyl 6-(quinolin-2-ylamino)nicotinate    -   (60) methyl        6-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (61) methyl        6-[(3-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (62) methyl        2-[(8-chloroquinolin-2-yl)amino]pyridine-3-carboxylate    -   (63) 8-methoxy-N-(4-methylpyridin-2-yl)quinolin-2-amine    -   (64) N-(4-methylpyridin-2-yl)-5-nitroquinolin-2-amine    -   (65) 2-N-(4-methylpyridin-2-yl)quinoline-2,8-diamine    -   (66) N-(4-methylpyridin-2-yl)-5-aminoquinolin-2-amine    -   (67) methyl        6-[(4-methylquinolin-2-yl)amino]pyridine-3-carboxylate    -   (68)        8-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (69) 2-[(8-chloroquinolin-2-yl)amino]pyridin-3-ol    -   (70)        8-chloro-N-[6-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (71) 6-chloro-N-(5-fluoropyridin-2-yl)quinolin-2-amine    -   (72) N-(6-ethylpyridin-2-yl)-3-methylquinolin-2-amine    -   (73) N-(5-fluoropyridin-2-yl)-3-methylquinolin-2-amine    -   (74)        3-methyl-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (75)        4-N-(8-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (76) N-(4-methoxyphenyl)quinolin-2-amine    -   (77) 8-chloro-N-(4-methoxyphenyl)quinolin-2-amine    -   (78) 4-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (79) N-(4-methoxyphenyl)-3-methylquinolin-2-amine    -   (80) 3-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (81)        1-N,1-N-dimethyl-4-N-(3-methylquinolin-2-yl)benzene-1,4-diamine    -   (82) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (83) N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (84) N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (85) N-(4-nitrophenyl)quinolin-2-amine    -   (86) N-(3-fluorophenyl)quinolin-2-amine    -   (87) 8-chloro-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (88) 8-chloro-N-(3-fluorophenyl)quinolin-2-amine    -   (89) 2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (90) 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (91)        3-methyl-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (92) 3-methyl-N-[3-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (93) 3-methyl-N-[2-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (94)        8-chloro-N-[2-methyl-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (95)        3-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (96) 6-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine    -   (97)        4-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}quinolin-1-ium        chloride    -   (98) 8-bromo-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (99) 8-fluoro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (100) 8-methyl-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (101) N-(4-butoxyphenyl)-8-chloroquinolin-2-amine    -   (102) N-(4-phenoxyphenyl)quinolin-2-amine    -   (103) 8-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (104)        8-chloro-N-[3-chloro-4-(trifluoromethoxy)phenyl]quinolin-2-amine    -   (105) N-(6-methylpyridin-2-yl)quinolin-3-amine    -   (106) N-(3-nitropyridin-2-yl)quinolin-3-amine    -   (107) N-(5-methylpyridin-2-yl)quinolin-6-amine    -   (108) N-(3-methoxypyridin-2-yl)quinolin-6-amine    -   (109) 6-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (110) 8-bromo-N-(pyrazin-2-yl)quinolin-2-amine    -   (111) 8-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (112) 8-chloro-N-(pyrazin-2-yl)quinolin-2-amine    -   (113) N-(pyrazin-2-yl)quinolin-2-amine    -   (114) 4-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (115) 3-methyl-N-(pyrazin-2-yl)quinolin-2-amine    -   (116) 8-fluoro-N-(pyrazin-2-yl)quinolin-2-amine    -   (117) 8-methoxy-N-(pyrazin-2-yl)quinolin-2-amine    -   (118) N-(pyridin-3-yl)quinolin-3-amine    -   (119) 8-chloro-N-(pyridin-4-yl)quinolin-2-amine    -   (120) N-(pyridin-4-yl)quinolin-2-amine    -   (121) N-(pyridin-4-yl)quinolin-3-amine    -   (122) N-[4-(trifluoromethoxy)phenyl]quinolin-3-amine    -   (123) N-(4-methoxyphenyl)quinolin-3-amine    -   (124) N-[4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (125) N-[2-methyl-4-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (126) N-[3-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (127) N-[2-(trifluoromethoxy)phenyl]quinoxalin-2-amine    -   (128) N-(pyrimidin-2-yl)quinolin-2-amine    -   (129) 8-chloro-N-(pyrimidin-2-yl)quinolin-2-amine    -   (130) 4-methyl-N-(pyrimidin-2-yl)quinolin-2-amine    -   (131) N-(pyrazin-2-yl)quinolin-6-amine    -   (132) N-(pyrazin-2-yl)quinolin-3-amine    -   (133) 6-methyl-N-(naphthalen-2-yl)pyridin-2-amine    -   (134) N-(naphthalen-2-yl)pyridin-2-amine    -   (135) N-(pyridin-2-yl)quinoxalin-2-amine    -   (136) N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (137) 6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile    -   (138) N-(6-methylpyridin-2-yl)quinoxalin-2-amine    -   (139)        N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine    -   (140) N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (141) N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine    -   (142) N-(pyrimidin-2-yl)quinoxalin-2-amine    -   (143)        4-N,4-N-dimethyl-7-N-[4-(trifluoromethoxy)phenyl]quinoline-4,7-diamine    -   (144)        4-(morpholin-4-yl)-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (145) 4-methoxy-N-(pyridin-2-yl)quinolin-7-amine    -   (146) 4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine    -   (147)        4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine    -   (148) 5,8-dimethyl-N-(5-methylpyridin-2-yl)isoquinolin-6-amine    -   (149)        5,8-dimethyl-N-(5-trifluoromethylpyridin-2-yl)isoquinolin-6-amine    -   (150) N-(4-methylpyridin-2-yl)-8-nitroquinolin-2-amine    -   (151) 6-chloro-N-(6-ethylpyridin-2-yl)quinolin-2-amine    -   (152) 6-chloro-N-(5-methylpyridin-2-yl)quinolin-2-amine    -   (153)        6-chloro-N-[5-(trifluoromethyl)pyridin-2-yl]quinolin-2-amine    -   (154) N2-(8-chloroquinolin-2-yl)-4-methylpyridine-2,3-diamine    -   (155) N-(4-butoxyphenyl)-3-methylquinolin-2-amine    -   (156)        4-N-(6-chloroquinolin-2-yl)-1-N,1-N-dimethylbenzene-1,4-diamine    -   (157) 8-chloro-N-(3-chloro-4-methoxyphenyl)quinolin-2-amine    -   (158)        N1-(8-chloroquinolin-2-yl)-4-(trifluoromethoxy)benzene-1,2-diamine    -   (159) N-(3-aminopyridin-2-yl)quinolin-3-amine    -   (160) 6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine    -   (161) N-(4-ethylpyridin-2-yl)quinoxalin-2-amine    -   (162) N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine    -   (163) N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine    -   (164) [2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol    -   (165) N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine    -   (166)        N-(4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)quinolin-7-amine    -   (167) 4-methoxy-N-[4-(trifluoromethoxy)phenyl]quinolin-7-amine    -   (168)        N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine    -   and their pharmaceutically acceptable salts.

Among said compounds, compounds (2), (3), (4), (5), (7), (8), (9), (10),(13), (15), (16), (17), (18), (25), (26), (28), (31), (32), (33), (34),(35), (36), (38), (39), (41), (42), (45), (59), (61), (82), (83), (86),(102), (105), (106), (107), (108), (109), (113), (120), (123), (125),(128), (135), (136), (137), (138), (142), (145), (146) and (147) are ofparticular interest.

The present invention therefore extends to compounds (2), (3), (4), (5),(7), (8), (9), (10), (13), (15), (16), (17), (18), (25), (26), (28),(31), (32), (33), (34), (35), (36), (38), (39), (41), (42), (45), (59),(61), (82), (83), (86), (102), (105), (106), (107), (108), (109), (113),(120), (123), (125), (128), (135), (136), (137), (138), (142), (145),(146) and (147) or one of its pharmaceutically acceptable salts for useas an agent for preventing, inhibiting or treating pathological ornonpathological conditions linked with premature aging.

Some of said preceding compounds are new and form part of the presentinvention: (2), (5), (7), (8), (10), (13), (15), (16), (18), (25), (26),(28), (31), (32), (33), (34), (35), (36), (38), (39), (41), (42), (59),(61), (82), (83), (86), (102), (105), (106), (107), (108), (109), (113),(125), (128), (135), (136), (137), (138), (142), (145), (146) and (147)or one of its pharmaceutically acceptable salts such as hydrochloride,hydrobromide, tartrate, fumarate, citrate, trifluoroacetate, ascorbate,triflate, mesylate, tosylate, formate, acetate and malate.

The compounds of formulae (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir) and (Iee) cancomprise one or more asymmetric carbon atoms. They can thus exist in theform of enantiomers or of diastereoisomers. These enantiomers,diastereoisomers and their mixtures, including the racemic mixtures, areencompassed within the scope of the present invention.

Among the compounds of formula (I), some of them are new and form partof the invention, as well as their pharmaceutically acceptable salts,such as hydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

According to a particular embodiment, the present invention encompassescompounds of formula (Ig)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

and when n and n′ are 1 and R is a hydrogen atom then R′ is not a —COOHgroup,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (If)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ih)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Il)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that R and R′ are not simultaneously a hydrogen atom,

or anyone of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Im)

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, and a (C₁-C₃)alkoxy group,

n is 1 or 2,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

with the proviso that when n and n′ are 1 and R is a hydrogen atom, R′is not a chlorine atom,

or anyone of its pharmaceutically acceptable salt.

For a sake of simplification, the following compounds and theircorresponding definitions are called “new compounds”.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ia), as such,

wherein:

R″ and n are as defined in formula (Ia),

n′ is 1,

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a —NO₂ group, a(C₁-C₃)fluoroalkoxy group and a (C₁-C₃)alkoxy group,

R′ is a hydrogen atom or a halogen atom or a group chosen among a(C₁-C₃)alkyl group, a —COOR₁ group, and a —CN group,

R₁ is a hydrogen atom or a (C₁-C₃)alkyl group:

with the proviso that

when R and R′ are not simultaneously a hydrogen atom,

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

when R′ is a hydrogen atom, R is not a bromine atom or a chlorine atom,

when R is a hydrogen atom, R′ is not a methyl or ethyl group, a —COOHgroup, a COOC₂H₅ group or a bromine atom, said bromine atom being inortho position of the bond linked to NR″,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ia), as such,

wherein:

R independently represent a hydrogen atom, a —NO₂ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)alkoxy group, a —CN group, a (C₁-C₃)alkyl group, a —COOR₁ group or a halogen atom,

R″ is as defined in formula (Ia),

R₁ is as defined above,

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃) alkyl group,

n′ is 1,

n is 1 or 2,

with the proviso that

when n is 1, R is not a methyl group in ortho or para position withrespect to Z, Z being N,

R is not a bromine atom or a chlorine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore preferably focuses on compounds of formula (Ia′), as such,

wherein:

R independently represent a hydrogen atom, a —COOR₁ group, a (C₁-C₃)alkyl group, —NO₂ group, a (C₁-C₃)fluoroalkyl group, a —CN group, ahalogen atom or a hydroxyl group,

R₁ is as defined above,

R″ is as defined in formula (Ia),

n is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ib), as such,

wherein:

R′ and R″ are as defined in formula (Ib),

n is 1, and

R is a hydrogen atom or a (C₁-C₃)fluoroalkoxy group,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ic), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a (C₁-C₃)fluoroalkyl group, a —CNgroup, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂ groupand a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

R is not a bromine atom when R′ is a hydrogen atom,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ic), as such,

wherein:

R is a hydrogen atom, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)alkyl group,a (C₁-C₃)alkoxy group, a —NO₂ group or a —COOR₁ group,

n, R″, n′ and R₁ are as defined in formula (Ic),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, and is preferablya hydrogen atom,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Id), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group and a —NR₁R₂ group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (I) and is advantageously a hydrogen atom,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

with the proviso that when R′ is a hydrogen atom, R is different from a—NO₂ group, a —NH₂ group or a —COOH group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Id), as such,wherein,

R is a hydrogen atom, a (C₁-C₃)alkyl group, a (C₁-C₃)alkoxy group or a(C₁-C₃)fluoroalkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, and advantageously ahydrogen atom,

R″ is as defined in formula (I) and is advantageously a hydrogen atom,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ie)

wherein:

-   -   R, R′, R″ n and n′ are as defined in formula (I),    -   with the proviso that    -   when R is a hydrogen atom, R′ is not a bromine atom,    -   or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ii′), as such,

wherein:

R₃ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a hydrogen atom, R₃ is not a methyl group or atrifluoromethyl group

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij′), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a hydrogen atom, R₄ is not a methyl group

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij″), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ij′″), as such,

wherein:

R₄ is a (C₁-C₃)fluoroalkyl group or a (C₁-C₃)alkyl group,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —NO₂ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group and a —CN group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

R″ is as defined above and is advantageously a hydrogen atom,

n′ is as defined above and is advantageously 1,

with the proviso that

when R′ is a chlorine atom or a hydrogen atom, R₄ is not an ethyl groupor a methyl group,

when R′ is a methyl group or a tertio-butyl group, R₄ is not a methylgroup,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ik), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and is advantageously 1,

n′ is 1 or 2,

R″ is as defined in formula (Ik),

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ik), as such,

wherein:

R is a hydrogen atom,

R″ is as defined in formula (Ik),

R′ is a hydrogen atom, a halogen atom or a (C₁-C₃) alkyl group,

n is 1 or 2, and is advantageously 1,

n′ is 1 or 2,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Io), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

when R is a hydrogen atom and n′ is 1, R′ is not a hydroxyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Io), as such,

wherein:

R is a hydrogen atom, a (C₁-C₃)alkyl group or a —CN group,

n is 1, 2 or 3,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group, and preferably is ahydrogen atom or a (C₁-C₃)alkyl group,

R₁ is as defined in formula (Io),

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ip), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

with the proviso that

R and R′ are not simultaneously a hydrogen atom,

when n and n′ are 2 then R and R′ are not simultaneously a methyl group.

or one of its pharmaceutically acceptable salt.

According to another particular embodiment, the present inventionencompasses compounds of formula (Ir), as such,

wherein:

R independently represent a hydrogen atom, a halogen atom or a groupchosen among a (C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

n is 1 or 2, and advantageously 1,

n′ is 1 or 2,

R′ is a hydrogen atom or a group chosen among a (C₁-C₃)alkyl group, ahalogen atom, a hydroxyl group, a —COOR₁ group, a —NO₂ group, a —NR₁R₂group, a (C₁-C₃)alkoxy group and a —CN group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

or one of its pharmaceutically acceptable salt.

Still according to this particular embodiment, the present inventionmore particularly focuses on compounds of formula (Ir), as such,

wherein:

R is a hydrogen atom or a (C₁-C₃)alkyl group,

R′ is a (C₁-C₃)alkoxy group or a —NR₁R₂ group,

R″ is a hydrogen atom or a (C₁-C₄)alkyl group,

n and n′ are 1,

R₁ and R₂ are independently a hydrogen atom or a (C₁-C₃)alkyl group,

or one of its pharmaceutically acceptable salt.

Among said compounds as such, compounds (1), (2), (5)-(8), (10)-(16),(18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121), (124)-(130),(132), (135)-(141), (143)-(147), (149)-(168) and their pharmaceuticallyacceptable salts are of particular interest.

The present invention therefore extends to compounds (1), (2), (5)-(8),(10)-(16), (18), (21)-(44), (46)-(75), (77)-(84), (86)-(119), (121),(124)-(130), (132), (135)-(141), (143)-(147), (149)-(168) and theirpharmaceutically acceptable salts, as such.

More preferably, compounds (1), (2), (5)-(7), (10)-(16), (18),(21)-(44), (46)-(74), (105)-(108), (124)-(130), (135)-(141),(145)-(147), (150)-(154), (159), (160)-(165), (168) and theirpharmaceutically acceptable salts are of particular interest.

The present invention therefore extends more preferably to compounds(1), (2), (5)-(7), (10)-(16), (18), (21)-(44), (46)-(74), (105)-(108),(124)-(130), (135)-(141), (145)-(147), (150)-(154), (159), (160)-(165),(168) and their pharmaceutically acceptable salts, such ashydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

Still more preferably, the present invention extends to compounds (2),(5), (7), (10), (13), (15), (16), (18), (25), (26), (28), (31)-(36),(38), (39), (41), (42), (59), (61), (105)-(108), (125), (128),(135)-(138), (145)-(147) and their pharmaceutically acceptable salts,such as hydrochloride, hydrobromide, tartrate, fumarate, citrate,trifluoroacetate, ascorbate, triflate, mesylate, tosylate, formate,acetate and malate.

The new compounds of the present invention, i.e. compounds of formula(Ia), (Ib), (Ic), (Id), (Ie), (Ik), (Ii′), (Ij″), (Ij′″), (Io), (Ip) and(Ir) and the specific compounds as listed above, are not only useful asagent for inhibiting, preventing or treating premature aging but canalso be used as agent for inhibiting, preventing or treating AIDS orcancer, and more particularly colorectal cancer, pancreatic cancer, lungcancer including non-small cell lung cancer, breast cancer, bladdercancer, gall bladder cancer, liver cancer, thyroid cancer, melanoma,uterine/cervical cancer, oesophageal cancer, kidney cancer, ovariancancer, prostate cancer, head and neck cancer and stomach cancer, etc.

The compounds of the present invention can be prepared by conventionalmethods of organic synthesis practiced by those skilled in the art. Thegeneral reaction sequences outlined below represent a general methoduseful for preparing the compounds of the present invention and are notmeant to be limiting in scope or utility.

The compounds of general formula (I) can be prepared according to scheme1 (above, see EMBODIMENT I). The chemical structures and spectroscopicdata of some compounds of formula (I) of the invention are illustratedrespectively in the following Table I (above) and Table II (above, seeEMBODIMENT I).

The following examples illustrate in detail the preparation of compounds(2), (3), (4), (7), (8), (26), (31), (82), (105), (113), (128), (135),(136), (137), (138), (142), (146), (13), (108), (16), (123), and (38)according to the invention. The structures of the products obtained havebeen confirmed by NMR spectra.

Embodiment III: Examples

Typical Procedure for Pd-Catalysed Aminations

To a solution of 2-chloro quinoline (82 mg, 0.5 mmol, 1 equiv) intert-butanol (2 mL) were added the amino pyridine derivative/aniline(0.55 mmol, 1.1 equiv), Cs₂CO₃ (456 mg, 1.4 mmol, 2.8 equiv), Xantphos(5.8 mg, 0.01 mmol, 2 mol %), Pd(OAc)₂ (2.2 mg, 0.01 mmol, 2 mol %). Thereaction mixture was heated at 90° C. and stirred for 20 hours underargon. The reaction mixture was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yieldcompounds (2), (3), (4) and (8).

Example 1 2-(Quinolin-2-ylamino)-isonicotinic Acid—(2) of Table I

¹H NMR (300 MHz, DMSO) δ 13.16 (s, 1H), 8.72 (d, J=5.2, 1H), 8.63 (d,J=9.0, 1H), 8.28-8.13 (m, 2H), 8.05 (d, J=8.0, 1H), 7.90 (t, J=7.5, 1H),7.74-7.67 (m, 2H), 7.67-7.59 (m, 2H).

MS (electrospray) m/z (%) 266.1 (100) [M+H]⁺.

Example 2 (4-Methyl-pyridin-2-yl)-quinolin-2-yl-amine—(3) of Table I

¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 8.21 (d, J=5.3, 2H), 7.95 (d,J=8.9, 1H), 7.89 (d, J=8.4, 1H), 7.67 (d, J=8.0, 1H), 7.62 (t, J=7.7,1H), 7.40-7.28 (m, 2H), 6.78 (d, J=5.1, 1H), 2.41 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 154.3, 153.3, 149.5, 147.3, 137.7, 129.8,127.6, 127.1, 124.6, 123.7, 118.7, 114.1, 113.4, 21.7.

MS (electrospray) m/z (%) 236.2 (100) [M+H]⁺.

Example 3 Pyridin-2-yl-quinolin-2-yl-amine—(4) of Table I

¹H NMR (300 MHz, CDCl₃) δ 8.38 (d, J=8.4, 1H), 8.31 (dd, J=1.0, 4.9,1H), 8.01 (d, J=8.9, 1H), 7.87 (d, J=8.4, 1H), 7.77-7.68 (m, 3H), 7.64(t, J=7.7, 1H), 7.36 (t, J=7.5, 1H), 7.31 (d, J=8.9, 1H), 6.94 (dd,J=5.0, 7.2, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 154.1, 153.1, 147.8, 147.3, 138.3, 137.8,129.9, 127.6, 127.2, 124.6, 123.8, 117.4, 114.0, 113.0.

MS (electrospray) m/z (%) 222.2 (100) [M+H]⁺.

Example 4 Quinolin-2-yl-(4-trifluoromethoxy-phenyl)-amine—(8) of Table I

¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J=8.8, 1H), 7.82 (d, J=8.4, 1H), 7.69(t, J=9.4, 3H), 7.62 (t, J=7.7, 1H), 7.34 (t, J=7.5, 1H), 7.23 (d,J=8.7, 2H), 6.92 (d, J=8.9, 1H), 6.74 (s, 1H).

¹³C NMR (75 MHz, CDCl₃) δ 153.9, 147.6, 144.4, 139.3, 138.1, 130.1,127.7, 127.1, 124.4, 123.7, 122.5, 122.2, 121.0, 119.1, 112.2.

MS (electrospray) m/z (%) 305.0 (100) [M+H]⁺.

According to route (A), the compound of formula (III) is placed in aprotic solvent such as tert-butanol. The compound of formula (IV) isthen added in a 1.1 molar ratio with respect to the compound of formula(III) in presence of an inorganic base, such as Cs₂CO₃ or K₂CO₃, in a2.8 molar ratio, in the presence of a diphosphine, such as Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), or X-Phos2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in a 2 mol %amount relative to the total amount of compound of formula (III), and inthe presence of a catalyst, such as Pd(OAc)₂, or Pd₂dba₃ in a 2 mol %amount relative to the total amount of compound of formula (III). Thereaction mixture is then heated at 90° C., and stirred during 20 hours,under argon. The reaction mixture is concentrated under reduced pressureand the resulting residue is diluted with ethyl acetate. The organicphase is then washed twice with water, dried on magnesium sulphate,filtered and concentrated under reduced pressure. The residue could thenbe purified by column chromatography on silica gel to yield purecompounds (7), (26), (31), (8), (82), (105), (113), (128), (135), (136),(137), (138), (142), (146).

According to route (B), the compound of formula (V) is placed in aprotic solvent such as tert-butanol. The compound of formula (VI) isthen added in a 1.1 molar ratio with respect to the compound of formula(V) in presence of Cs₂CO₃ in a 2.8 molar ratio, in the presence ofXantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) in a 2 mol %amount relative to the total amount of compound of formula (V), and inthe presence of a Pd(OAc)₂, in a 2 mol % amount relative to the totalamount of compound of formula (V). The reaction mixture is then heatedat 90° C., and stirred during 20 hours, under argon. The reactionmixture is concentrated under reduced pressure and the resulting residueis diluted with ethyl acetate. The organic phase is then washed twicewith water, dried on magnesium sulphate, filtered and concentrated underreduced pressure. The residue could then be purified by columnchromatography on silica gel to yield pure compound (13), (108), (16),(123), (38).

Example 5: Compound (7) of Table I

According to route (A), a mixture of 2-chloroquinoline (1.3 g),2-amino-5-cyanopyridine (1.1 g), Pd(OAc)₂ (36.5 mg), XantPhos (94 mg)and Cs₂CO₃ (7.4 g) in 32 mL of t-BuOH gave compound (7) (1.6 g).

Example 6: Compound (26) of Table I

According to route (A), a mixture of 2,6-dichloroquinoline (98.5 mg),6-amino-3-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (26) (92.3 mg).

Example 7: Compound (38) of Table I

According to route (B), a mixture of 2-aminoquinoline (79.2 mg),3-bromo-2-methoxypyridine (71.5 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (38) (73.5 mg).

Example 8: Compound (31) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-amino-3-picoline (55 μL), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (31) (87.1 mg).

Example 9: Compound (8) of Table I

According to route (A), a mixture of 2-chloroquinoline (1.1 g),4-(trifluoromethoxy)aniline (1.0 mL), Pd(OAc)₂ (31.4 mg), XantPhos (80.9mg) and Cs₂CO₃ (6.4 g) in 28 mL of t-BuOH gave compound (8) (1.3 g).

Example 10: Compound (82) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-methyl-4-(trifluoromethoxy)aniline (81 μL), Pd(OAc)₂ (2.2 mg),XantPhos (5.8 mg) and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound(82) (64 mg).

Example 11: Compound (13) of Table I

According to route (B), a mixture of 3-aminoquinoline (79 mg),2-bromo-5-methylpyridine (101 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (13) (84.4 mg).

Example 12: Compound (105) of Table I

According to route (A), a mixture of 3-bromoquinoline (103.5 mg),6-amino-3-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (105) (66.5 mg).

Example 13: Compound (108) of Table I

According to route (B), a mixture of 6-aminoquinoline (79.0 mg),2-bromo-3methoxypyridine (94.0 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (108) (75.9 mg).

Example 14: Compound (16) of Table I

According to route (B), a mixture of 6-aminoquinoline (79.3 mg),2-bromo-6methylpyridine, Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃(456 mg) in 2 mL of t-BuOH gave compound (16) (81.2 mg).

Example 15: Compound (113) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),aminopyrazine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃(456 mg) in 2 mL of t-BuOH gave compound (113) (60.7 mg).

Example 16: Compound (123) of Table I

According to route (B), a mixture of 3-bromoquinoline (103.5 mg),p-anisidine (67.7 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) and Cs₂CO₃(456 mg) in 2 mL of t-BuOH gave compound (386) (65 mg).

¹H NMR (300 MHz, CDCl₃) δ 8.62 (d, J=2.8, 1H), 7.98 (d, J=7.4, 1H),7.61-7.54 (m, 1H), 7.45 (ddd, J=1.9, 4.9, 7.1, 3H), 7.18 (d, J=8.9, 2H),6.94 (d, J=8.9, 2H), 5.86 (s, 1H), 3.84 (s, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 156.26, 144.27, 143.25, 139.18, 134.42, 129.25, 129.18, 127.24,126.40, 126.04, 123.03, 115.13, 114.26, 55.79.

Example 17: Compound (128) of Table I

According to route (A), a mixture of 2-chloroquinoline (81.5 mg),2-aminopyrimidine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (128) (53.3 mg).

Example 18: Compound (135) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-aminopyridine (51.7 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (135) (47.7 mg).

Example 19: Compound (136) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-amino-3methylpyridine (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (136) (35.4 mg).

Example 20: Compound (137) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-amino-5-cyanopyridine (65.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg)and Cs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (137) (79.6 mg).

Example 21: Compound (138) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),6-amino-2-picoline (59.4 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (138) (89.4 mg).

Example 22: Compound (142) of Table I

According to route (A), a mixture of 2-chloroquinoxaline (82.0 mg),2-aminopyrimidine (52.3 mg), Pd(OAc)₂ (2.2 mg), XantPhos (5.8 mg) andCs₂CO₃ (456 mg) in 2 mL of t-BuOH gave compound (142) (47.0 mg).

¹H NMR (300 MHz, CDCl3) δ 10.07 (s, 1H), 8.57 (d, J=4.7, 2H), 8.04 (d,J=7.8, 1H), 7.83 (d, J=7.9, 1H), 7.68 (t, J=8.6, 1H), 7.58 (t, J=7.4,1H), 6.92 (t, J=4.6, 1H).

MS (ESI) [M+H]+=224

Example 23: Compound (146) of Table I

According to route (A), a mixture of 4-methoxy-7-chloro-quinoline*(500.0 mg), 2-amino-4-methylpyridine (0.310 g) XPhos (123.0 mg), K₂CO₃(1.41 g) and Pd2dba3 (118.0 mg) in 14 mL of t-BuOH gave compound 146(500 mg).

Preparation of 4-methoxy-7-chloro-quinoline

Into a 1-Neck round-bottom flask 4,7-dichloro-quinoline, (5.0 g, 0.025mol) was dissolved in 1.25 M of hydrogen chloride in methanol (16 mL).The mixture was heated to reflux overnight. After 16 hours of heating,the mixture was cooled to room temperature. The mixture was concentratedunder reduce pressure. The solid was dissolved in sodium bicarbonate (50mL, 0.6 mol) (saturated aqueous solution) and the solution was extractedwith Ethyl acetate (100 mL, 1 mol) (4×25 ml). The organic layer waswashed with sodium chloride (50 mL, 0.8 mol) (saturated aqueoussolution) (2×25 ml) and was dried over Na₂SO₄ and was concentrated underreduce pressure to give 4-methoxy-7-chloro-quinoline (4.5 g pale yellowpowder).

MS (ESI) [M+H]+=194

Example 24

Pharmacological Data

The compounds of the invention have been the subject of pharmacologicaltests which have demonstrated their relevance as active substances intherapy and in particular for preventing, inhibiting or treatingpathological or nonpathological conditions linked with premature aging.

The following materials and methods have been used.

Material and Methods

Minigene Constructs Reproduce Aberrant Splicing of LMNA mRNA, Leading toHGPS

In order to identify and characterize the factor(s) involved in the useof the cryptic 5′ splice site in exon 11 of LMNA, an ex vivo system hasbeen developed that recapitulates this splicing event. The cloning ofmutant and wild type constructs (FIG. 1A, for schematic representation)were carried out using a TOPO-TA cloning vector in which is inserted aminigene containing 142 nts of β-Globin first exon, 130 nts β-Globinfirst intron, 270 nts LMNA exon 11 either wild type or mutant, 322 ntsintron 11 and 46 nts exon 12. Using this system the splicing eventactivated by the GGC>GGT mutation in exon 11 of the LMNA gene wasconfirmed by transfections in cultured HeLa cells (FIG. 1B, lanes WT andMut) as well as in vitro splicing experiments using in vitro synthesizedradiolabeled substrate (Panel C). Transfection experiments of minigeneconstructs containing or not the point mutation demonstrated that likein Progeria patients the mutation leads to a switch from the use of thenormal splice site (intron 11 position 1) to the use of the crypticsplice site upstream of the mutation (exon 11 position 1819) (FIG. 1,Panel C, compare lanes WT and Mut). Note that following a kinetics of invitro splicing for 150 minutes, aberrant splicing is observed with thewild type substrate (FIG. 1C, Lanes 1-7), implying that the mutation isnot a perquisite for cryptic splice site usage. The mutation simplyenhances the efficacy of selection of this cryptic splice site (FIG. 1C,Lanes 8-15).

Advantage has been taken of the luciferase system. The luciferase assayis an extremely sensitive and rapid assay. Linear results are seen overat least eight orders of magnitude of enzyme concentration. Moreover,the luciferase assay is well suited for high-throughput applications. Toconduct a Mid-throughput screening (MTS) for compounds repressing LMNAaberrant splicing, we have constructed a plasmid in which exon 11,intron 11 and part of exon 12 of LMNA gene were fused with luciferasecDNA (FIG. 2). Both wild type (WtLMNA-luc)(SEQ ID NO: 1) and mutant(MutLMNA-luc)(SEQ ID NO: 2) substrate harbouring exon 11 mutation havebeen constructed. In these constructs we have generated a singleinitiation codon in exon 11 such as correct splicing will lead toluciferase expression, while aberrant splicing will skip the initiationcodon and thereby prevent luciferase expression. After transfection inHeLa cells, Luciferase assays (FIG. 2B) and RT-PCR (FIG. 2C) indicatethat WtLMNA-luc produces predominantly wild type splicing and largeamount of luciferase activity, whereas MutLMNA-luc recapitulate theaberrant splicing profile with reduced luciferase expression (FIGS. 2 Band C, compare Wt and Mut). In order to use this system in MTS, we havegenerated a stable 293 cell lines containing a single integrated copy ofluciferase reporter containing LMNA mutation (MutLMNA-luc cell line)using the flp system from INVITROGEN. This system allows us to perform aMTS for compounds able to enhance luciferase activity.

Plasmids Constructs.

LMNA sequences (1278 bp of exon 11, intron 11 and 46 bp of exon 11) werePCR-amplified from either control or patient's cells genomic DNA withspecific primer PCR fragments were purified with Concert Rapid PCRpurification system (Invitrogen) and subcloned at the BamHI and EcoRIrestriction sites of the pSpβm3S1 plasmid containing the βGlobincassette (Labourier et al., 1999—Recognition of exonic splicing enhancersequences by the Drosophila splicing repressor RSF1. Nucleic Acids Res.27, 2377-2386) to give the βGlo3S1LMNAwt and βGlo3S1LMNAmut constructs.The chimeric βGlo-LMNA sequences were then inserted into thepcDNA3.1D/V5-His-TOPO vector (Invitrogen) to be used in transfection andin vitro splicing experiments. A single initiation codon ATG was kept inexon 11 of LMNA and LMNA sequences described above were fused at their3′ end to Fyrefly luciferase cDNA (LMNAlucWT) in order that removal ofintron 11 generates a transcript that encode a fusion protein harbouringluciferase activity, whereas usage of the cryptic splice site of mutatedexon 11 (LMNAlucMut) will remove the initiation codon preventingluciferase expression. Both sequences were cloned in pcDNA3 Flp-Invector (Invitrogen).

Transfection and RT-PCR.

HeLa cells transfections with splicing reporter constructs wereperformed with lipofectAMINE 2000 reagent (Invitrogen) according to themanufacturer's instructions. Twenty four hours after transfection, totalRNA was purified with RNA-PLUS™ (Quantum Bioprobe). First strand cDNAwas synthesized from 2 μg of RNA with the Amersham-Pharmacia Firststrand cDNA synthesis kit. For PCR analyses, 1/15 of the reaction wasamplified with Taq polymerase (Invitrogen). The cycle number was kept toa minimum to maintain linearity. PCR products were separated on a 1.5%agarose gel containing ethidium bromide and visualized under UV light.

A stable 293 cell line containing a single copy of LMNAlucMut minigenewas obtained using the Flp-In system from (Invitrogen) according tomanufacture procedure. Several clones were obtained and only one clonewas used to screen the whole chemical library (293FLP LMNA LUC cells#8).

Nuclear Extracts Preparation, Splicing and Complementation Assays.

HeLa cells nuclear extracts were prepared according to (Dignam et al.,1983—Eukaryotic gene transcription with purified components. MethodsEnzymol. 101, 582-598). Pre-mRNA were synthesized by in vitrotranscription in the presence of 20 units of T7 RNA polymerase, 1 μg ofthe suitable linearized plasmids and 5 μM [α-³²P] UTP (3000 Ci/mmol) in25 μl reactions according to manufacturer conditions. In vitrotranscripts were quantified by Cerenkov counting. Splicing reactionswere performed under standard conditions as described previously (Taziet al., 1986—A protein that specifically recognizes the 3′ splice siteof mammalian pre-mRNA introns is associated with a small nuclearribonucleoprotein. Cell 47, 755-766). Splicing products were analyzed byelectrophoresis on 7% denaturing polyacrylamide gels and revealed byautoradiography.

Material

293FLP LMNA LUC cells #8

Hygromycin B at 50 mg/mL (invitrogen 10687-010)

Dulbecco's Modified Eagle Medium (D-MEM) (1×)+GlutaMAX, liquid(invitrogen 31966-021)

Dulbecco's Phosphate Buffered Saline (D-PBS) (1×), liquid (invitrogen14190-169)

Trypsin 2.5%

Foetal calf serum (FCS)

Penicillin (P)

Streptomycin (S)

Passive Lysis Buffer (PLB) (5×) (Promega)

Bradford Reagent (B6916)

Luciferase assay buffer

96 Well Plate sterile, V-shape (greiner bio-one 651180)

96 Well Microplate sterile, flat bottom (greiner bio-one 655180)

96 Well Microplate, flat bottom, Chimney Well (greiner bio-one 655075)

CellTiter 96® AQ_(ueous) One Solution (Promega G3581)

Methods

First Day

Plate at 500 μM

In a 96 Well Plate sterile, V-shape one put 0.5 μl of drug compounds at50 mM and then add 49.5 μl of 10% DMSO.

Replica Plate

One pipets 47 μl of drug at 500 μM and adds 2004, of DMEM+Hygromycin B.At this stage the concentration of drug compound is 10 μM. One sharesout 100 μl in a 96 Well Microplate sterile, flat bottom (further calledluciferase plate) and 50 μl in other one (further called toxicityplate).

One washes 293FLP LMNA LUC cells once with D-PBS then adds 1 ml trypsinEDTA. Incubation at 37° C. for 2-3 minutes is proceeded. Then one adds 9ml DMEM (with 10% FCS, P/S).

One takes 7 μl of cell suspension and adds 14 μL blue trypan to countcells. Meanwhile cell suspension is centrifugated at 1200 rpm for 5minutes at room temperature (RT).

Cell concentration is brought at 105 cells per ml with DMEM+Hygromycin Bto have 104 cells per 100 μl.

Luciferase Plate

100 μl of suspension cells is added (at 104 cells per 100 μl) so finalconcentration of compounds is 5 μM.

Toxicity Plate

50 μl of suspension cells is added. The final concentration of compoundsis 5 μM.

48 Hours Later

Toxicity Plate

20 μl of CellTiter 96® AQueous One Solution is added per well.Incubation is proceeded at 37° C. for 2 h. Absorbance is red at 490 nm.

Luciferase Plate

Medium of the wells is gently removed then washed once by adding slowly150 μl of D-PBS 1×. D-PBS is removed. 40 μl of PLB 1× is added andincubated at RT for 30 minutes.

20 μl of cell lysate is put in a 96 Well Microplate, flat bottom,Chimney Well. 70 μl of luciferin assay substrate is added. One readluminescence for 1 second.

200 μl of Bradford reagent is added on the remaining cell lysate (20μl). Incubation is proceeded at RT for 30 min then one can readabsorbance at 595 nm. A range has to be made. Usually 5 differentconcentrations are tested: 0.25, 0.5, 0.75, 1 and 1.25 mg/ml.

Results

The compounds according to the present invention demonstrate an increaseof luciferase activity ranging between 3 and 7 fold compared to controluntreated MutLMNA-luc cell line.

In particular, the results are as follows for some of the compoundsaccording to the present invention.

Compound number Increase of luciferase activity 7 3.33 34 4.18 36 3.0631 5.07 26 6.20 8 3.35 105 3.25 135 4.58 136 5.20 137 4.64 138 8.22 1424.47 2 3.77 3 4.54 4 4.43 5 2.02 17 3.66 18 2.85 25 3.49 28 2.99 32 2.9633 2.14 35 2.74 38 5.81 39 4.29 41 3.32 42 3.87 45 3.08 59 2.49 61 2.0482 3.41 83 2.74 86 2.77 102 2.06 9 2.47 10 2.01 13 3.46 106 2.77 15 2.1716 4.56 107 2.20 108 4.57 109 2.79 113 2.28 120 2.38 123 2.94 125 2.59128 3.08 145 3.87 146 4.18 147 2.94

Therefore, the result of the tests carried out on the compoundsdisclosed in the present invention show that said compounds may beuseful to inhibit, prevent and/or treat diseases with premature agingand that are likely related to an aberrant splicing of the nuclear laminA gene. Among all, said disease may include Hutchinson Guilford ProgeriaSyndrome (HGPS), progeria, premature aging associated with HIVinfection, muscular dystrophy, Charcot-Marie-Tooth disorder, Wernersyndrome, but also atherosclerosis, insulin resistant type II diabetes,cataracts, osteoporosis and aging of the skin such as restrictivedermopathy.

For this purpose an effective amount of a said compound may beadministered to a patient suffering from premature aging and inparticular from progeria, and from the previous cited diseases.

The present invention is also related to the use of at least a compoundchosen among a compound of anyone of formula (I), (I′), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io),(Ip), (Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168)as defined above, or one of its pharmaceutically acceptable saltsaccording to the present invention for the manufacture of apharmaceutical composition intended for the treatment of pathological ornonpathological conditions linked with premature aging and in particularprogeria.

The present invention also encompasses pharmaceutical compositionscomprising at least a compound chosen among new compounds of formula(Ia), (Ia′), (Ic), (Id), (Ii′), (Ij″), (Ij′″), (Ik), (Io), (Ip) and (Ir)as defined above and compounds (1), (2), (5)-(7), (10)-(16), (18),(21)-(44), (46)-(74), (105)-(108), (124)-(130), (135)-(141),(145)-(147), (150)-(154), (159), (160)-(165), (168), as defined above orany pharmaceutically acceptable salt thereof.

Thus, these pharmaceutical compositions contain an effective amount ofsaid compound, and one or more pharmaceutical excipients.

The aforementioned excipients are selected according to the dosage formand the desired mode of administration.

In this context they can be present in any pharmaceutical form which issuitable for enteral or parenteral administration, in association withappropriate excipients, for example in the form of plain or coatedtablets, hard gelatine, soft shell capsules and other capsules,suppositories, or drinkable, such as suspensions, syrups, or injectablesolutions or suspensions, in doses which enable the daily administrationof from 0.1 to 1000 mg of active substance.

The present invention is also related to the use of at least a compoundchosen among a compound of anyone of formula (I), (I′), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (Io),(Ip), (Iq), (Ir) or (Iee) as defined above, and compounds (1) to (168)as defined above, or one of its pharmaceutically acceptable saltsaccording to the present invention for the manufacture of apharmaceutical composition intended for inhibiting, preventing and/ortreating pathological or nonpathological conditions linked withpremature aging and in particular progeria but also all the previouslisted diseases.

The present invention further relates to a method of treatment ofpatients suffering form premature aging or anyone of the previous listeddisease, which comprises at least a step of administration to a patientsuffering thereof of an effective amount of a compound of anyone offormula (I), (I′), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii),(Ij), (Ik), (Il), (Im), (Io), (Ip), (Iq), (Ir), (Iee) and (1) to (168)or one of its pharmaceutically acceptable salts.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of: a compound of formula(Ic):

wherein: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a(C₁-C₃)fluoroalkyl group, a —NO₂ group, a —NR₁R₂ group, or a(C₁-C₃)alkoxy group, R₁ and R₂ are independently a hydrogen atom or a(C₁-C₃)alkyl group, n is 1 or 2, n′ is 1 or 2, R″ is a hydrogen atom ora (C₁-C₄)alkyl group, R′ is a hydrogen atom, a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group and a (C₁-C₃)alkoxy group, with the provisothat: R and R′ are not simultaneously a hydrogen atom, and R is not abromine atom when R′ is a hydrogen atom; a compound of formula (Id):

wherein: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, ora —NR₁R₂ group, R₁ and R₂ are independently a hydrogen atom or a(C₁-C₃)alkyl group, n is 1 or 2, n′ is 1 or 2, R″ is a hydrogen atom ora (C₁-C₄)alkyl group, and R′ is a hydrogen atom, a (C₁-C₃)alkyl group, a—NO₂ group, a —NR₁R₂ group, or a (C₁-C₃)alkoxy group, with the provisothat when R′ is a hydrogen atom, R is different from a —NO₂ group, a—NH₂ group, or a —COOH group; a compound of formula (Io):

wherein: R independently represents a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group where the (C₁-C₃)alkyl group is optionallymono-substituted by a hydroxyl group, a —CN group, a hydroxyl group, a—COOR₁ group, a (C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a—NO₂ group, a —NR₁R₂ group, or a (C₁-C₃)alkoxy group, R₁ and R₂ areindependently a hydrogen atom or a (C₁-C₃)alkyl group, n is 1, 2 or 3,n′ is 1 or 2, R′ is a hydrogen atom, a halogen atom, a (C₁-C₃)alkylgroup, a (C₁-C₃)fluoroalkyl group, a —COOR₁ group, a —NR₁R₂ group, a(C₁-C₃)alkoxy group, or a —CN group, and R″ is a hydrogen atom or a(C₁-C₄)alkyl group; and a compound of formula (Ir):

wherein: R independently represent a hydrogen atom, a halogen atom, a(C₁-C₃)alkyl group, a —CN group, a hydroxyl group, a —COOR₁ group, a(C₁-C₃)fluoroalkyl group, a (C₁-C₃)fluoroalkoxy group, a —NO₂ group, a—NR₁R₂ group, or a (C₁-C₃)alkoxy group, R₁ and R₂ are independently ahydrogen atom or a (C₁-C₃)alkyl group, n is for 2, n′ is 1 or 2, R′ is ahydrogen atom, a halogen atom, a (C₁-C₃)alkyl group, a —COOR₁ group, a—NO₂ group, a —NR₁R₂ group, a (C₁-C₃)alkoxy group, or a —CN group, andR″ is a hydrogen atom or a (C₁-C₄)alkyl group.
 2. The compound, or apharmaceutically acceptable salt thereof, of claim 1, wherein thecompound is a compound of the formula (Ir):


3. The compound, or a pharmaceutically acceptable salt thereof, of claim2, wherein the compound is a compound of the formula (Ic):


4. The compound, or a pharmaceutically acceptable salt thereof, of claim3, wherein the compound is a compound of the formula (Id):


5. The compound, or a pharmaceutically acceptable salt thereof, of claim4, wherein the compound is a compound of the formula (Io):


6. The compound of claim 5, wherein the pharmaceutically acceptable saltis selected from the group consisting of a hydrochloride salt, ahydrobromide salt, a tartrate salt, a fumarate salt, a citrate salt, atrifluoroacetate salt, an ascorbate salt, a triflate salt, a mesylatesalt, a tosylate salt, a formate salt, an acetate salt, and a malatesalt.
 7. A compound, or a pharmaceutically acceptable salt thereof,selected from the group consisting of: (10)(3-Methoxy-pyridin-2-yl)-quinolin-3-yl-amine (11)Quinolin-3-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (12)(5-Nitro-pyridin-2-yl)-quinolin-3-yl-amine (13)(5-Methyl-pyridin-2-yl)-quinolin-3-yl-amine (14)2-(Quinolin-3-ylamino)-isonicotinic acid (15)Quinolin-6-yl-(5-trifluoromethyl-pyridin-2-yl)-amine (16)(6-Methyl-pyridin-2-yl)-quinolin-6-yl-amine (105)N-(6-methylpyridin-2-yl)quinolin-3-amine (106)N-(3-nitropyridin-2-yl)quinolin-3-amine (107)N-(5-methylpyridin-2-yl)quinolin-6-amine (108)N-(3-methoxypyridin-2-yl)quinolin-6-amine (135)N-(pyridin-2-yl)quinoxalin-2-amine (136)N-(4-methylpyridin-2-yl)quinoxalin-2-amine (137)6-(quinoxalin-2-ylamino)pyridine-3-carbonitrile (138)N-(6-methylpyridin-2-yl)quinoxalin-2-amine (139)N-(4-methylpyridin-2-yl)-3-(trifluoromethyl)quinoxalin-2-amine (140)N-(3,5-dichloro-4-methylpyridin-2-yl)quinoxalin-2-amine (141)N-(4-methyl-3-nitropyridin-2-yl)quinoxalin-2-amine (145)4-methoxy-N-(pyridin-2-yl)quinolin-7-amine (146)4-methoxy-N-(4-methylpyridin-2-yl)quinolin-7-amine (147)4-N,4-N-dimethyl-7-N-(4-methylpyridin-2-yl)quinoline-4,7-diamine (159)N-(3-aminopyridin-2-yl)quinolin-3-amine (160)6-chloro-N-(4-methylpyridin-2-yl)quinoxalin-2-amine (161)N-(4-ethylpyridin-2-yl)quinoxalin-2-amine (162)N-(5-bromo-4-methylpyridin-2-yl)quinoxalin-2-amine (163)N-(4,6-dimethylpyridin-2-yl)quinoxalin-2-amine (164)[2-(quinoxalin-2-ylamino)pyridin-4-yl]methanol (165)N-(4-methyl-5-nitropyridin-2-yl)quinoxalin-2-amine and (168)N-(4-methylpyridin-2-yl)-4-(morpholin-4-yl)quinolin-7-amine.
 8. Thecompound of claim 7, wherein the pharmaceutically acceptable salt isselected from the group consisting of a hydrochloride salt, ahydrobromide salt, a tartrate salt, a fumarate salt, a citrate salt, atrifluoroacetate salt, an ascorbate salt, a triflate salt, a mesylatesalt, a tosylate salt, a formate salt, an acetate salt, and a malatesalt.
 9. A pharmaceutical composition comprising at least one compound,or a pharmaceutically acceptable salt thereof, of claim 6 and apharmaceutically acceptable carrier.
 10. A pharmaceutical compositioncomprising at least one compound, or a pharmaceutically acceptable saltthereof, of claim 7 and a pharmaceutically acceptable carrier.